?INGESTION
?DIGESTION
?ABSORPTION
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?TRANSPORTATION?UPTAKE BY TISSUES
2. LIPOLYSIS: LIPID CATABOLISM
q FATTY ACID OXIDATION
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q KETONE BODY METABOLISM3. LIPOGENESIS:
q LIPID BIOSYNTHESIS
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q DE NOVO BIOSYNTHESIS OF FATTY ACIDS4. LIPOPROTEIN METABOLIM/
TRANSPORTATION OF LIPIDS
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5. DISORDERS ASSOCIATED TO LIPID
METABOLISM
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INGESTION OF DIETARY LIPIDS/EATING OF DIETARY LIPIDS
?Lipid is the chief
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constituent of humanfood.
Why To Eat Dietary Lipids?
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OR
Importance Of Ingesting
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Dietary LipidsImportance Of Ingesting Dietary Lipids:
? To obtain TAG a secondary source of energy
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for body tissues.? To get source of Essential Fatty acids /PUFAs
structural components of tissues.
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? To get source of Fat Soluble Vitamins
(Vitamin A,D,E and K) associated with Fatty
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foods.? To improve taste of recipes.
? To increase palatability and satiety value.
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?Thus daily consumption of
dietary lipids is essential
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?For the maintenance ofnormal , growth, health and
reproduction of human
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body.
In What
Amount & Form
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The Dietary Lipids
to be Eaten?
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? The daily consumption of dietaryLipids by human beings varies and
depends upon:
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?Dietary habits of an individual
?Economic status of a family
RDA OF DIETARY LIPIDS
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?Per day quantity of dietaryLipids for an adult
individual is:
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?60-80 grams of dietary
Lipids in his/her diet.
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FORMS AND SOURCES OFDIETARY LIPIDS
Dietary Forms Of Lipids
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? The dietary ingested Lipids contain fol owingforms of Lipids:
?Triacylglycerol (TAG):Predominant
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form of dietary Lipid - 98%.
?Phospholipids
?Cholesterol Ester
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?Fat soluble Vitamins: are soluble in Fathence associated with fatty foods.
? The quality of ingested
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Lipids should containadequate amounts of
Essential Fatty Acids
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(PUFAs).
?The ideal ratio of dietary
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Fatty acids in a TAG shouldbe :
PUFA : MUFA : SFA
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1 : 1 : 1
Trans Fats are Detrimental To Health
? The sources of dietary Lipids
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should be free from Trans Fatty
acids/less than 1%.
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? Trans Fatty acids are not readilymetabolized by human body.
? Trans Fats increases the risk of
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Atherosclerosis.
Dietary Rich Sources Of Lipids
?The dietary rich sources
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of Lipids
?Obtained from foods of
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Plant and Animal origin.Sources Of Plant Lipids
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q Plant Oils: Peanut ,Safflower
,Sunflower, Olive, Mustard Oils,
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Margarine etc.qNuts: Peanuts , Walnuts , Cashew
,Almonds, Sesame ,Pine etc
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Sources Of Animal Lipids?Milk
?Ghee, Butter , Cheese
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?Egg Yolk
?Fish
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?Animal-Fat ,Meat , Liver and BrainCharacteristics Of Food Fat Sources
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Visible Fat
. Butter, Margarine, Salad oils and
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dressing, Shortening Fat MeatInvisible Fat
. Cheese, Cream portion of
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homogenized milk, Egg yolk, Nuts,
Seeds, Olives.
Digestion Of Dietary Lipids In GIT
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Digestion Of Dietary Lipids
Is
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Cleavage Of Ester BondsPresent In Various Lipid Forms
By
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Lipases/Lipolytic Enzymes
In
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Different Parts Of GITInsignificant Digestion
Of Dietary Lipids
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Occurs in Mouth and Stomach? Though the Salivary juice
contains Lingual Lipase and
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Gastric juice contains Gastric
Lipase .
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? The digestion of dietary Lipids inmouth and stomach is negligible.
Insignificant Digestion Of Lipids In
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Mouth and Stomach Due to:?No optimal pH in juices for optimal
activity of Enzyme Lipases to act on
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dietary Lipids of Mouth and Stomach
? No Emulsification Process in Mouth
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and GIT?As non polar Lipid droplets are
insoluble in the juices.
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?Dietary Lipids do not have
contact with polar and soluble
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Enzymes present in theaqueous phase of salivary and
gastric juices.
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?Since there is no contact ofdietary insoluble forms of Lipids
and soluble forms of Enzymes.
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?There is no cleaving of the Ester
bonds of Lipid structures in the
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salivary and gastric juices fordigestion of Lipids in mouth and
stomach.
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Significant and Complete
Digestion
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Of Dietary LipidsOccurs In
Smal Intestine
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After Emulsification
What Is Emulsification?
Emulsification is an Essential
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Prerequisite Physicochemical
Process in Smal intestine
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ToInitiate and Complete
Significant Digestion of
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Dietary Lipids
?Emulsification is a
Physicochemical process
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?Which forms Emulsions
from the dietary ingested
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Lipids.? Emulsification takes place in the
lumen of smal intestine.
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? This is very essential process to
occur before the digestion of
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dietary Lipids.Requirements
Of
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EmulsificationTo Form Emulsions
? Emulsification takes place to form
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Emulsions with the help of Emulsifying
agents:
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?Emulsifying Agents/Surfactants:? Bile Salts (Sodium Glycocholate, Sodium
Taurocholate)
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? Amphipathic Lipids (present in diet)
?Mechanical force :
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? Provided by peristaltic movement ofintestine.
? During the process of
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Emulsification there isdispersion of large droplets
of Fats/Oils
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? Into smal , miscible droplets
which are termed as
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Emulsions.?Emulsions have non polar
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lipids (TAG) in center?Covered with a peripheral
layer of Bile salts and
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Amphipathic Lipids.
Requirement Of Bile
In Smal Intestine
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For Lipid Digestion and
Absorption
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? Bile is a greenish fluidproduced in Liver.
? It is concentrated and is
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stored in Gal bladder.
? Carried through bile duct
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? Later secreted in Smalintestine
?Cholecystokinin (CCK)
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and Secretin?Stimulates the:
Gal bladder to contract
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and release bile.
Composition Of Bile
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? Bile is an Alkaline solutioncomposed of:
?Bile Salts (Surfactant)
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?Bilirubin (Bile Pigment)
?Cholesterol
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?Lecithin?Bile acids
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Bile AcidRole Of Bile Salts In Emulsification
?Name Of Bile salts :
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?Sodium Glycocholate?Sodium Taurocholate
?Bile salts present in the
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bile have detergent like
action
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?Bile salts areemulsifying agents
?They are responsible for
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fat Emulsification
? Bile salts present in Bile and
dietary Amphipathic Lipids by
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their detergent like action:
?Reduces surface tension
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?Increases surface area ofFats/Oil and made them
miscible with aqueous phase.
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? Emulsions bring non polar
dietary Lipids in close
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contact with Lipid digestingEnzymes present in aqueous
phase of intestinal juices.
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Significance Of Emulsification? Emulsification facilitate in the digestion of
dietary ingested Lipids in small intestine by:
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?Reduces surface tension, increasing surface
area of Lipids
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?Forms Emulsions?Improves the miscibility of non polar Lipids
TAG in aqueous phase.
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?Brings contact of dietary Lipids with Lipiddigesting enzymes.
?Facilitates cleavage of Ester bonds of
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dietary Lipids.
Emulsions formed by Bile salts, Triacylglycerols and pancreatic lipase.
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Action Of SpecificLipid Digesting Enzymes
(Lipases)
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in Smal Intestine
? Dietary forms of Lipids are
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digested:?By the action of specific Lipid
digesting enzymes
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?Present in Pancreatic and
intestinal juice
?Digestion of Lipids is
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cleavage of Ester
bonds present in their
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structures.Digestion Of Triacylglycerol
(TAG)
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By Enzyme Pancreatic Lipase
? Dietary Fat/Oil which is chemically
TAG is the predominant ingested
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Lipid form.
? TAG is predominantly and
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significantly digested in smalintestine
? After the process of Emulsification.
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Action Of Pancreatic Lipase
? Digestion of Triacylglycerol is
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cleaving of ester bonds present in itsstructure.
? Triacylglycerol in small intestine is
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specifically acted upon by enzyme
Pancreatic Lipase.
Colipase Facilitates
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Pancreatic Lipase Activity
? Pancreatic Colipase
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?Is activated by Trypsin?Colipase interacts with
Triacylglycerol and Pancreatic Lipase
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?Displaces Bile to allow recycling?Improves activity of Pancreatic
Lipase
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Role Of Pancreatic Colipase
? Secreted from Pancreas as
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Procolipase? Activated (cleaved) by
Trypsin
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? Colipase anchors Lipase to
the Emulsion.
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? One Colipase to one Lipase(i.e., 1:1 ratio)
?Pancreatic Lipase digest
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TAG
?By specifically cleaving first
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and third ester bonds ofTAG structure.
? Pancreatic Lipase attack TAG at 1 and 3 positions of
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Ester bonds.G Fatty Acid1
G
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l
l
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yLipase
y
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Fatty Acid1
c
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c Fatty Acid2 H
+
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e Fatty Acid
2
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220
e
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r
r
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Fatty Acid3ol
ol
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Fatty Acid3
Triacylglycerol
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2-Monoacylglycerol2 Free Fatty Acids
? The products of TAG digestion
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? By Pancreatic Lipase activityare:
?Free Fatty acids
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?Monoacylglycerol (2MAG)Bile Salts
Dietary Fat
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Lipase 2-Monoacylglycerol(large TG droplet)
+ 2 FFA
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Lipid emulsion
Triacylglycerol
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Colipase Pancreatic Lipase
Optimum PH 6 Cleaves 1st and 3 rd ester
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bond of TAG
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Free Fatty acids + 2-Monoacylglycerol(Fatty acid esterified at C2 of Glycerol)
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Action of Non SpecificLipid Esterases
? Non specific Lipid Esterases act
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on 2-MAG /Retinol Ester.? It cleaves the ester bonds and
releases Free Fatty acid and
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Glycerol/Retinol respectively.
2-Monoacylglycerol
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Non Specific Esterase
Cleaves Ester bond at C2
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Free Fatty acid + Glycerol
Digestion Of Phospholipids
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by
Action of Phospholipase A2
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andLysophospholipase
? The pancreatic juice enzymes
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Phospholipase A2 and
Lysophospholipase digests
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dietary Phospholipids.Phospholipid
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Phospholipase A2
Cleaves Ester bond at C2 of PL
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Lysophospholipid+ Free Fatty acid
Lysophospholipid
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Lysophospholipase
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Cleaves Ester bond at C1Glycerophosphorylcholine+ Free Fatty
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acid
? Phospholipase A2 cleaves second
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position ester bond of Phospholipidand form Lysophospholipid and Free
Fatty acid.
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? Lysophospholipid is then acted by
Lysophospholipase which cleaves ester
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bond at C1 to generate:Glycerophosphorylcholine and Free
Fatty acids.
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Digestion Of Cholesterol EsterBy
Cholesterol Esterase
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Cholesterol Ester
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Cholesterol EsteraseCleaves Ester bond at C3
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Free Cholesterol+ Free Fatty acid
End Products Of Lipid Digestion
? 5 Simple Forms as End products of Lipid Digestion
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1. Free Fatty acids
2. Glycerol
3. 2-Monoacylglycerol (2-MAG)
4. Glycerophosphoryl-Choline
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5. Free CholesterolAbsorption
of
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Dietary End Products
Of Lipid Digestion
?Absorption of end
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products of Lipid
digestion takes place in
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smal intestine.? The rate of absorption of
different types of Lipids differ.
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?Pork fat is almost absorbed
completely.
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?Castor oil is not at al absorbed.Theories Of Lipid Absorption
? Absorption of Lipids is a complex
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mechanism and various theories areproposed to explain its mechanism.
?Lipolytic Theory
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?Partition Theory?Bergstorm Theory (Most Recent and
accepted one)
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?The simple forms ofLipids as digestive end
products are ready for
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absorption.
Mechanism Of Lipid Absorption
? Bile Salts play an important role
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in absorption of digestive end
products of dietary Lipids.
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? Bile salts help in formation ofMixed micel es.
?Mixed Micelle is a
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aggregation of digestive
end products of dietary
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Lipids with a peripherallayer of Bile Salts.
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?The efficiency of Lipidabsorption depends upon:
?The quantity of Bile salts
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?Which solubilizes andform Mixed Micelles.
Mixed Micel e Formation
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? Mixed Micel e is a complex of Lipidmaterials and Bile salts soluble in water
?It contains Bile salts, end products of
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Phospholipids & Cholesterol at periphery
of a Mixed Micel es.
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?2-Monoacylglycerol, Free fatty acids andfat-soluble Vitamins in center of Mixed
Micel es.
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Mixed Micel e Formation
? In the Mixed Micel e the non
polar long chain fatty acids
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are at the center
? At the periphery are
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Amphipathic Lipid moietiesand Bile salts.
? Bile salts and Amphipathic
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Lipids of Mixed Micelle
? Exert a solubilizing effect on
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non polar Lipid moieties andhelp in their absorption.
? Mixed Micel es then get attached
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to the intestinal mucosal celmembrane.
? This help the Lipid end products to
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slowly cross the mucosal
membrane.
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? Bile salts of Mixed Micelles donot cross the intestinal mucosal
cel membrane.
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? They get retained in intestinal
lumen and later get recycled.
?The Bile salts are
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reabsorbed further down
the Gastrointestinal tract
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(in the ileum)? Bile salts are transported
back to the Liver through
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enterohepatic circulation
? Final y recycled and
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secreted back into thedigestive tract
Re-Esterification of Simple Lipids
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ORResynthesis Of Complex
Forms Of Lipids
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In Intestinal Mucosal Cells
?Once the simpler forms of
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Lipids enter the intestinalmucosal cells
?They are resynthesized
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into complex forms of
Lipids in the intestinal
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mucosal cells.? Free Fatty acid (FFA) + Glycerol Monoacylglycerol
? MAG +FFA Diacylglycerol
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? Diacylglycerol + FFATriacylglycerol
? Glycerophosphorylcholine + FFAs
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Phospholipid
? Cholesterol +FFA Cholesterol Ester
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? Note the resynthesizedcomplex Lipids in intestinal
mucosal cel s
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? Are usual y different from
those ingested through diet.
?The dietary absorbed
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Lipids in intestinal
mucosal cells are then
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mobilized out asLipoproteins.
Formation Of Lipoprotein
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Chylomicrons
In Intestinal Mucosal Cells
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For TheTransportation Of
Dietary Lipids
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?The Lipids of dietary originpresent in intestinal
mucosal cells are mostly
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non polar (TAG) and
hydrophobic in nature.
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? The transport of these dietaryLipids through aqueous phase of
lymph and blood is
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? Facilitated through formation of
a Lipoprotein -Chylomicron in
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intestinal mucosal cells.? Lipoprotein Chylomicron is
formed in intestinal mucosal
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cel s by? Aggregation of dietary
ingested, digested and
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absorbed Lipids and
Apoprotein (ApoB48).
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? Chylomicron structure has thenon polar Lipids aggregated at
center, the Amphipathic Lipids
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and Apoproteins are at
periphery.
?Chylomicron has 98% of
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TAG (dietary origin)
?1% other Lipids and
?1% Proteins.
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? Chylomicrons from intestinal
mucosal cells are first released in
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Lacteals (Lymph vessels) ofLymphatic system
? Which then enters the systemic
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blood circulation via Thoracic
duct.
--- Content provided by FirstRanker.com ---
? Thus Chylomicron serve as a
vehicle for transporting the
--- Content provided by FirstRanker.com ---
exogenous forms of dietary Lipids? From Smal intestine to Liver via
aqueous phase of Lymph and
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Blood.
Lipid Digestion Absorption and
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Transport
Mechanism Of
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Lipid Absorption
Simple diffusion
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ExocytosisShort and
medium
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chain fatty
acids
--- Content provided by FirstRanker.com ---
Overviewof Lipid
Digestion
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and
Absorption
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Absorption of Lipids
Absorption of fat.
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Transportation OfChylomicrons
Through Blood Circulation
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Action OF Enzyme Lipoprotein Lipase
On Lipoproteins
--- Content provided by FirstRanker.com ---
(Chylomicrons and VLDL)
Unlike
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Plasma Lipid ClearanceOR
Role Of Clearing Factor
--- Content provided by FirstRanker.com ---
? Unlike Carbohydrates (Glucose) and
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Protein (Amino acids) who use
enterohepatic circulation to reach first
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to Liver.? Most Lipids do use systemic circulatory
system.
--- Content provided by FirstRanker.com ---
? This allows Lipids to be cleared by the
whole body and avoids overwhelming
--- Content provided by FirstRanker.com ---
the Liver with Lipids.? Most of the absorbed Lipids
from GIT mucosal cel s do not
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directly enter the bloodstream.
? Instead, they are packaged
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into Chylomicrons and first
released into the lymph.
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? The lymph dumps into the Aortic arch (atthe Thoracic duct's connection with the left
Sub Clavian vein) .
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? Where it then is transported through the
blood stream to be cleared and taken up
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by:?Adipocytes
?Liver
?Muscle
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? Clearance of Lipoproteinsfrom circulation
? Is mediated by an enzyme
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase (LPL)
acting upon TAG of
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Lipoproteins.? Nascent (New) Chylomicrons released
from intestinal mucosal cells are
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circulated first through lymph and
then in systemic blood circulation.
? Nascent Chylomicrons in
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blood circulation get matured
? After the receipt of Apo C I
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and ApoE from HDL.? Apo C I of Mature Chylomicron then
stimulates an enzyme Lipoprotein Lipase
--- Content provided by FirstRanker.com ---
(LPL)
? LPL associated in endothelial lining of
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blood vessels, of Adipose, Heart,and Skeletal Muscle tissue, as well as in
Lactating Mammary glands.
--- Content provided by FirstRanker.com ---
? Stimulated Lipoprotein Lipase thenacts upon the TAG of Lipoproteins
(Chylomicron and VLDL).
--- Content provided by FirstRanker.com ---
? Lipoprotein Lipase hydrolyze the TAG
of Lipoproteins to Free Fatty acids and
--- Content provided by FirstRanker.com ---
Glycerol.? Released Glycerol and Free Fatty acids
enter the adjacent Adiposecytes.
--- Content provided by FirstRanker.com ---
? Glycerol and FFAs entered
in Adipocytes are
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transformed into TAG.? TAG is storage form of
Fatty acids
--- Content provided by FirstRanker.com ---
? TAG serve as a reserve
source of energy.
?The LPL by its activity
--- Content provided by FirstRanker.com ---
on Chylomicrons
reduces its content of
--- Content provided by FirstRanker.com ---
TAG.? The Chylomicrons after the
action of LPL reaching to
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Liver are
? Maximal y reduced with TAG
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content and now termed asChylomicron Remnant.
? The Chylomicron remnant in
--- Content provided by FirstRanker.com ---
comparison to NascentChylomicron is
? Smal er in size, and has very
--- Content provided by FirstRanker.com ---
less percentage of dietary
TAG, associated to it.
--- Content provided by FirstRanker.com ---
? Chylomicron remnants get fixedto their specific receptors
present on Hepatocytes and get
--- Content provided by FirstRanker.com ---
internalized.
? The internalized Chylomicron
--- Content provided by FirstRanker.com ---
remnants inside the Liver getsfurther metabolized.
? Lipoprotein Lipase is also
--- Content provided by FirstRanker.com ---
termed as Clearing Factor? Since Lipoprotein Lipase clears
Lipaemic sera(Chylomicrons)
--- Content provided by FirstRanker.com ---
in post absorptive phase.
LPL Activity On Chylomicrons
--- Content provided by FirstRanker.com ---
? In Post absorptive phase most of theblood Chylomicrons are transformed to
Chylomicron remnants
--- Content provided by FirstRanker.com ---
? By the Lipoprotein Lipase activity,
? The released moieties from Chylomicrons
--- Content provided by FirstRanker.com ---
are internalized by Adiposecytes andHepatocytes
? This clears the circulating Chylomicrons
--- Content provided by FirstRanker.com ---
from blood.
v Defect In Lipoprotein Lipase
Do not clear blood
--- Content provided by FirstRanker.com ---
Lipoproteins
Accumulates Chylomicrons
--- Content provided by FirstRanker.com ---
and VLDL in blood circulationHeparin Is a Coenzyme For
Lipoprotein Lipase
--- Content provided by FirstRanker.com ---
? MI patients are administered
with Heparin injections
--- Content provided by FirstRanker.com ---
? Which may stimulate theLipoprotein Lipase activity
? And clear blood with elevated
--- Content provided by FirstRanker.com ---
Chylomicrons and VLDL.
--- Content provided by FirstRanker.com ---
Transport of Short Chain Fatty Acids
And
--- Content provided by FirstRanker.com ---
Medium Chain Fatty AcidsIs Different From
Long Chain Fatty Acids
--- Content provided by FirstRanker.com ---
? Transport of Short and Medium chain
Fatty acids
--- Content provided by FirstRanker.com ---
?These enter portal blood directlyfrom enterocytes
?Transported after bound to Albumin
--- Content provided by FirstRanker.com ---
in blood
?Albumin?FFA complex
?FFA which are internalized in Liver
--- Content provided by FirstRanker.com ---
?Oxidized to liberate ATPs
OR
--- Content provided by FirstRanker.com ---
?Elongated and used for TAGformation
? Long-chain Fatty acids
--- Content provided by FirstRanker.com ---
?Transported in the form of
Chylomicrons
--- Content provided by FirstRanker.com ---
?Drain into the Lymphatics via theLacteal in Mammals
?Enter blood stream at the Thoracic
--- Content provided by FirstRanker.com ---
duct
Important Role Of Bile Salts In
Lipid Digestion and Absorption
--- Content provided by FirstRanker.com ---
? Bile Salts are formed in Liver
from Bile acids.
--- Content provided by FirstRanker.com ---
? Bile Salts are mixed and carriedthrough Bile via Common Bile
Duct(CBD) to small intestine.
--- Content provided by FirstRanker.com ---
? Bile Salts in intestine helps inEmulsification of dietary Lipids to
form Emulsions and Facilitates Lipid
--- Content provided by FirstRanker.com ---
Digestion.
? Later Bile Salts form Mixed Micel es
--- Content provided by FirstRanker.com ---
and facilitates the absorption ofdigestive end products Lipids.
Disorder Related
--- Content provided by FirstRanker.com ---
To Lipid
Digestion and Absorption/
--- Content provided by FirstRanker.com ---
SteatorrhoeaSteatorrhoea
? Steatorrhoea is a Malabsorption
--- Content provided by FirstRanker.com ---
condition? Where there is no digestion and no
absorption of dietary Lipids in GIT
--- Content provided by FirstRanker.com ---
? Dietary ingested Lipids are excreted
out through feces
--- Content provided by FirstRanker.com ---
? Steatorrhoea leads to Fatty stoolsCauses Of Steatorrhoea
? The basic cause to suffer from
--- Content provided by FirstRanker.com ---
Steatorrhoea is:
?Absence of emulsifying
--- Content provided by FirstRanker.com ---
agents- Bile salts in the smalintestine.
?Absence of specific Enzymes
--- Content provided by FirstRanker.com ---
for Lipid digestion.
Thus Any Condition Affecting,
Synthesis, Secretion and
--- Content provided by FirstRanker.com ---
Transport of Bile to Intestine
leads to Steatorrhoea
--- Content provided by FirstRanker.com ---
? Extensive Liver damageaffects Bile Synthesis.
? Celiac Diseases: Sprue,
--- Content provided by FirstRanker.com ---
Crohn's Disease
? Surgical removal of intestine
? Obstructive Jaundice
--- Content provided by FirstRanker.com ---
? Obstruction due to
narrowing of bile duct after
--- Content provided by FirstRanker.com ---
surgeries? Obstruction of CBD due to
Gal Stones
--- Content provided by FirstRanker.com ---
Biochemical Alterations in
Steatorrhoea
? No/Less Bile Salts in small
--- Content provided by FirstRanker.com ---
intestine
? No/Less Emulsification of
--- Content provided by FirstRanker.com ---
dietary Lipids? No/Less Emulsions formed
? No/Less Contact of Lipids with
--- Content provided by FirstRanker.com ---
Lipases? No/Less digestion of dietary Lipids
? No/Less formation of Mixed
--- Content provided by FirstRanker.com ---
Micelles? No/Less absorption of dietary
Lipids
--- Content provided by FirstRanker.com ---
? More excretion of dietary Lipids
through feces.
Consequences Of Steatorrhoea
--- Content provided by FirstRanker.com ---
? In Steatorrhoea person suffers from
deficiency of essential Fatty acids
--- Content provided by FirstRanker.com ---
and Fat Soluble Vitamins.? Body lacks exogenous TAG as
secondary source of Energy.
--- Content provided by FirstRanker.com ---
? Body lacks from Exogenous source of
Phospholipids and Cholesterol.
Diagnosis OF Steatorrhoea
--- Content provided by FirstRanker.com ---
? Determination Of Fecal Fat
? Microscopical y (Fat Globules present)
? Quantitatively (Gravimetric Method)
--- Content provided by FirstRanker.com ---
Chyluria? Chylomicrons in Urine is termed as
Chyluria.
--- Content provided by FirstRanker.com ---
? Abnormal condition where
lymphatic drainage system opens
--- Content provided by FirstRanker.com ---
in urinary tract.? Urine appears milky
? Chyluria occurs in Filariasis.
--- Content provided by FirstRanker.com ---
Chylothorax
? Chylomicrons in Pleural
--- Content provided by FirstRanker.com ---
fluid is termed asChylothorax.
? Abnormal y Thoracic duct
--- Content provided by FirstRanker.com ---
opens in pleural cavity.
Overview Of Lipid Metabolism
vLipid metabolism involves:
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vLipolysis
vLipogenesis
vLiver and Adipose tissue play a
--- Content provided by FirstRanker.com ---
central role in Lipid metabolism.vAdipose tissue is the main store
--- Content provided by FirstRanker.com ---
house of Triacylglycerol in the body.vFatty acids are reduced
compound oxidized/catabolized
--- Content provided by FirstRanker.com ---
to Acetyl CoA
vFatty acids are biosynthesized
--- Content provided by FirstRanker.com ---
using Acetyl CoA as a precursor.Lipid Metabolism
--- Content provided by FirstRanker.com ---
What Is Lipolysis?
OR
--- Content provided by FirstRanker.com ---
Role Of Hormone Sensitive Lipase(HSL)
--- Content provided by FirstRanker.com ---
?In a well fed conditionTAG is stored as reserve
source of energy in
--- Content provided by FirstRanker.com ---
Adiposecytes.
Fat Storage in White Adipose Tissue
? Lipolysis occurs in emergency
--- Content provided by FirstRanker.com ---
conditions
? Lipolysis is the break down of
--- Content provided by FirstRanker.com ---
Depot Fat-Triacylglycerol(TAG)? Into Free Fatty acids and
Glycerol
--- Content provided by FirstRanker.com ---
? By enzyme activity of Hormone
sensitive Lipase
--- Content provided by FirstRanker.com ---
TriacylglycerolIn Adipocytes Hormone Sensitive Lipase
--- Content provided by FirstRanker.com ---
Cleaves Ester bonds
Glycerol+ Free Fatty acid
--- Content provided by FirstRanker.com ---
?During Lipolysis the
secondary source of
--- Content provided by FirstRanker.com ---
energy TAG?Stored as depot Fat gets
utilized.
--- Content provided by FirstRanker.com ---
Diagrammatic View Of LipolysisConditions Of Lipolysis
? Lipolysis significantly and efficiently occurs :
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?In emergency fasting condition
?In between long hours after meals
--- Content provided by FirstRanker.com ---
?When the primary source of energyGlucose go below normal range in blood
?In presence of Hormones Glucagon or
--- Content provided by FirstRanker.com ---
Epinephrine
?By activity of Hormone Sensitive Lipase
? The Enzyme Hormone Sensitive
--- Content provided by FirstRanker.com ---
Lipase of Adipocytes is stimulated
By Hormones:
--- Content provided by FirstRanker.com ---
? Glucagon and Epinephrinemediated via cAMP.
?On Lipolysis the Free Fatty
--- Content provided by FirstRanker.com ---
acids and Glycerol are
mobilized out of
--- Content provided by FirstRanker.com ---
adipocytes in bloodcirculation.
End Products Of Lipolysis
--- Content provided by FirstRanker.com ---
?Free Fatty Acids?Glycerol
Fate Of Glycerol After Lipolysis
? Glycerol (polar moiety)released in
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emergency condition during
Lipolysis
--- Content provided by FirstRanker.com ---
? Is carried through blood andenters in Liver and Muscles.
Fate Of Glycerol In Muscles
--- Content provided by FirstRanker.com ---
Glycerol Enter intoGlycolytic Pathway
(In Muscles)
--- Content provided by FirstRanker.com ---
Glycerol
--- Content provided by FirstRanker.com ---
Glycerol Kinase
Glycerol-3-Phosphate
--- Content provided by FirstRanker.com ---
Glyceraldehyde-3-PO4
?Glycerol of Lipolysis is
--- Content provided by FirstRanker.com ---
metabolized via Glycolysis
in Muscles
? Glycerol in muscles is
--- Content provided by FirstRanker.com ---
Phosphorylated to Glycerol-3-PO4
? Glycerol-3-PO4 is further oxidized
--- Content provided by FirstRanker.com ---
to Glyceraldehyde-3-PO4? Thus Glyceraldehyde-3-PO4 in
Muscles make its entry in
--- Content provided by FirstRanker.com ---
Glycolysis
? Further gets metabolized to
--- Content provided by FirstRanker.com ---
generate energy (ATP) formuscle activity.
Fate Of Glycerol In Liver
--- Content provided by FirstRanker.com ---
Glycerol Of LipolysisIs a Precursor For Gluconeogenesis
(In Liver)
--- Content provided by FirstRanker.com ---
Glycerol Is Used For Glucose
Biosynthesis In Liver
? Glycerol of Lipolysis is metabolized
--- Content provided by FirstRanker.com ---
via Gluconeogenesis in Liver
? Glycerol in Liver is Phosphorylated
--- Content provided by FirstRanker.com ---
to Glycerol-3-PO4 by GlycerolKinase
? Glycerol-3-PO4 is further oxidized to
--- Content provided by FirstRanker.com ---
? Glyceraldehyde-3-PO4 and isomerized
to DHAP
--- Content provided by FirstRanker.com ---
? This then is converted to Glucose.? Thus Glyceraldehyde-3-PO4
in Liver make its entry in
--- Content provided by FirstRanker.com ---
Gluconeogenesis and? Further gets metabolized to
produce Glucose.
--- Content provided by FirstRanker.com ---
?Glucose formed in Liver is
mobilized out into blood
--- Content provided by FirstRanker.com ---
and?Supplied to Brain and
Hepatocytes in fasting
--- Content provided by FirstRanker.com ---
condition.
Fate Of Free Fatty Acids
After Lipolysis
--- Content provided by FirstRanker.com ---
? Non polar Long Chain Free Fatty
acids released in blood
--- Content provided by FirstRanker.com ---
circulation after Lipolysis are nottransported on its own.
? Needs the help of a polar moiety.
--- Content provided by FirstRanker.com ---
Polar Moiety AlbuminTransports
Long Chain Free Fatty Acids
--- Content provided by FirstRanker.com ---
In Blood
Released After Lipolysis
--- Content provided by FirstRanker.com ---
? Long chain Free Fatty acids areuncharged/nonpolar/hydrophobic
? They are linked with polar Protein
--- Content provided by FirstRanker.com ---
moiety Albumin
? FFA-Albumin complex get
--- Content provided by FirstRanker.com ---
transported through bloodcirculation.
? Albumin remain in the blood
--- Content provided by FirstRanker.com ---
circulation? Free Fatty acids make its
entry in Muscle cel s.
--- Content provided by FirstRanker.com ---
Fatty Acids In Muscles
Oxidized To Liberate Energy
--- Content provided by FirstRanker.com ---
(ATP)? Free Fatty acids are highly reduced
compounds.
--- Content provided by FirstRanker.com ---
? Free Fatty acids entered in Musclesduring emergency condition
? After Lipolysis, are oxidized to
--- Content provided by FirstRanker.com ---
liberate chemical form of energy
ATP.
--- Content provided by FirstRanker.com ---
?Thus after Glucose FreeFatty acid serve as
secondary source of
--- Content provided by FirstRanker.com ---
energy to body tissues.
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
208
Oxidation Of Fatty Acids
--- Content provided by FirstRanker.com ---
ORCatabolism/Degradation
Of Fatty Acids
--- Content provided by FirstRanker.com ---
How Fatty Acid Oxidation
Serve As
--- Content provided by FirstRanker.com ---
Energy Source?? Fatty acids are an important
secondary source of energy to
--- Content provided by FirstRanker.com ---
body.?Since Fatty acids are reduced
compounds
--- Content provided by FirstRanker.com ---
?Possess CH2-CH2 hydrocarbon bonds
with bond energy in their structures
--- Content provided by FirstRanker.com ---
? Oxidation of Fatty acid /Catabolism orbreakdown of Fatty acid is by:
?Removal of Hydrogen from hydrocarbon
--- Content provided by FirstRanker.com ---
chain (CH2-CH2).
?Which are temporarily accepted by
--- Content provided by FirstRanker.com ---
Coenzymes?With formation of reduced Coenzymes
?Reoxidation of these reduced Coenzymes
--- Content provided by FirstRanker.com ---
by entry in ETC /Oxidative Phosphorylationgenerates ATP.
?Oxidation of the Hydrocarbon
--- Content provided by FirstRanker.com ---
bonds of fatty acid chain makesthem weaker
?Easy Cleavage of hydrocarbon
--- Content provided by FirstRanker.com ---
bonds of Fatty acid
?Which helps in shortening of
--- Content provided by FirstRanker.com ---
the long Fatty acid chain.Types Of
Fatty Acid Oxidation
--- Content provided by FirstRanker.com ---
1. Oxidation Based On Type Of Carbon Atom? Alpha() Oxidation(Phytanic acid ?Branched Chain FA)
? Beta () Oxidation (Most Predominant)
--- Content provided by FirstRanker.com ---
? Omega() Oxidation (When defect in Oxidation)
2.Oxidation Based On Number Of Carbon
--- Content provided by FirstRanker.com ---
Atom? Beta Oxidation of Even Carbon
Chain Fatty acid oxidation
--- Content provided by FirstRanker.com ---
? Beta Oxidation of Odd Chain
Fatty Acid Oxidation
--- Content provided by FirstRanker.com ---
? Very Log Chain Fatty Acid(VLCFA) Oxidation
3.Oxidation Based On Nature Of
--- Content provided by FirstRanker.com ---
Bonds? Oxidation of Saturated
Fatty acids
--- Content provided by FirstRanker.com ---
? Oxidation of Unsaturated
Fatty acids
--- Content provided by FirstRanker.com ---
4.Oxidation Based On Cel ular Site? Mitochondrial Fatty acid
Oxidation
--- Content provided by FirstRanker.com ---
? Endoplasmic Reticulum Fatty
acid Oxidation
--- Content provided by FirstRanker.com ---
? Peroxisomal Fatty acidOxidation
The General
--- Content provided by FirstRanker.com ---
Pattern To StudyMetabolic Pathways
? Synonyms/Different Names of Pathway.
--- Content provided by FirstRanker.com ---
? What is the Pathway ? (In brief)? Where the pathway occurs/Location?
(Organ/Cellular site)
? When pathway occurs/Condition?
(well fed/emergency/aerobic/anaerobic)
--- Content provided by FirstRanker.com ---
? What type Of Pathway?(Catabolic/Anabolic)
? Requirements for the Pathway
(If Anabolic Pathway)
--- Content provided by FirstRanker.com ---
? How the pathway Occurs/Stages/Steps?(Type of Rxn , Enzymes ,Coenzymes)
? Why the Pathway occurred?
(Significance of Pathway)
--- Content provided by FirstRanker.com ---
? Precursor, intermediates, byproducts andend products of metabolic Pathway.
? Energetics of the pathway/Net ATP Use
--- Content provided by FirstRanker.com ---
and Generation
? Interrelation ships with other Pathways
? Regulation of Pathway :Modes of regulation.
--- Content provided by FirstRanker.com ---
? Regulatory Hormone/ RegulatoryEnzyme/Modulators.
? Inborn Error of the Metabolic Pathway
--- Content provided by FirstRanker.com ---
How Palmitic Acid isCompletely Oxidized In Human Body?
Calculate Its Energetics
--- Content provided by FirstRanker.com ---
Beta Oxidation
Of
--- Content provided by FirstRanker.com ---
Even CarbonSaturated Fatty Acid
--- Content provided by FirstRanker.com ---
At Mitochondrial Matrix
Historical Aspects Of
Beta Oxidation of Fatty Acids
--- Content provided by FirstRanker.com ---
? Albert Lehninger showed that
? Oxidation of Fatty acids
--- Content provided by FirstRanker.com ---
occurred in the Mitochondria.? Knoop showed that Fatty
acid is oxidized and
--- Content provided by FirstRanker.com ---
degraded by removal of 2-Cunits
? F. Lynen and E. Reichart
--- Content provided by FirstRanker.com ---
showed that the 2-C unit
released is Acetyl-CoA, but
--- Content provided by FirstRanker.com ---
not free Acetate.Beta Oxidation Of Palmitate (C16)
What Is Beta Oxidation
--- Content provided by FirstRanker.com ---
Of Fatty Acid ?Definition Of Oxidation
of Fatty acid
--- Content provided by FirstRanker.com ---
? Oxidation of a Fatty acid at theBeta Carbon atom/C3 (-CH2)
? Beta Oxidation of Fatty Acid is
--- Content provided by FirstRanker.com ---
the most predominant type ofFatty acid oxidation.
? Most of the Fatty acids in the
--- Content provided by FirstRanker.com ---
cel s get oxidized and catabolized
via Beta Oxidation of Fatty Acid
--- Content provided by FirstRanker.com ---
b-Oxidation OF Fatty Acid? b-oxidation of Fatty acids is the
catabolic/ degradative , energy
--- Content provided by FirstRanker.com ---
generating metabolic pathway of
Fatty acids
--- Content provided by FirstRanker.com ---
? It is referred to as the b-oxidationpathway, because oxidation occurs at
the b-carbon (C3) of a Fatty acid.
--- Content provided by FirstRanker.com ---
? During Beta oxidation of
Fatty acid (-CH2) of Beta
--- Content provided by FirstRanker.com ---
position is oxidized and
? Transformed to Carbonyl
--- Content provided by FirstRanker.com ---
atom (-C=O)? The oxidized and transformed Beta
--- Content provided by FirstRanker.com ---
positioned -C-H2 to -C=O duringthe steps of Beta Oxidation Proper.
? Makes the bond between Alpha
--- Content provided by FirstRanker.com ---
and Beta Carbon Atom weaker
and cleavable to release 2Carbon
--- Content provided by FirstRanker.com ---
unit Acetyl-CoA.The Weak bond between Alpha and Beta
Carbon Atom is Cleaved to release
--- Content provided by FirstRanker.com ---
2Carbon Unit Acetyl-CoA
? With a removal of 2-C units
--- Content provided by FirstRanker.com ---
there is shortening the Fatty
acid chain.
--- Content provided by FirstRanker.com ---
? The 2-C units released afterthe steps of Beta Oxidation is
Acetyl-CoA (active Acetate)
--- Content provided by FirstRanker.com ---
which enters TCA for its
complete oxidation.
--- Content provided by FirstRanker.com ---
b-Oxidation OF Fatty Acid
Is a Catabolic Energy Producing
--- Content provided by FirstRanker.com ---
PathwayOrgans Involved with
Beta Oxidation Of Fatty Acid
--- Content provided by FirstRanker.com ---
?Skeletal Muscles?Heart
?Hepatocytes
?Kidney
--- Content provided by FirstRanker.com ---
Cel ular Site ForBeta Oxidation Of Fatty Acid
?Cytosol
--- Content provided by FirstRanker.com ---
(Activation of Fatty acid)
?Mitochondrial Matrix
(Beta Oxidation Proper)
--- Content provided by FirstRanker.com ---
b-Oxidation pathway:Fatty acids are degraded in the Mitochondrial Matrix via
the b-Oxidation Pathway.
--- Content provided by FirstRanker.com ---
Organs Which Do Not Operate
Beta Oxidation Of Fatty Acid
Remember In
--- Content provided by FirstRanker.com ---
Brain and Erythrocytes
Fatty Acids
--- Content provided by FirstRanker.com ---
Do Not ServeAs A Source Of Energy
?Free Fatty acids cannot
--- Content provided by FirstRanker.com ---
cross the blood brain
barrier
--- Content provided by FirstRanker.com ---
?Hence Fatty acids donot enter Brain to get
oxidized.
--- Content provided by FirstRanker.com ---
? Beta Oxidation proper of Fattyacid takes place in
Mitochondrial matrix
--- Content provided by FirstRanker.com ---
? Since mature RBC's has no
Mitochondria
--- Content provided by FirstRanker.com ---
? Hence no oxidation of Fattyacids occurs in Erythrocytes.
? In emergency conditions
--- Content provided by FirstRanker.com ---
?Since Brain and Erythrocytes
cannot oxidize Fatty acids and
--- Content provided by FirstRanker.com ---
use as energy source.?These organs has to depend
only on Glucose for getting
--- Content provided by FirstRanker.com ---
energy for their vitality.
Type Of Metabolic Pathway
? Beta Oxidation Of a Fatty acid is
--- Content provided by FirstRanker.com ---
a:
?Catabolic Pathway
?Degradative Pathway
--- Content provided by FirstRanker.com ---
?Energy generating metabolicpathway in emergency phase
Condition Of Its Occurrence
--- Content provided by FirstRanker.com ---
? Usually Beta Oxidation of Fatty acids
efficiently occurs after Lipolysis.
--- Content provided by FirstRanker.com ---
? When there is low use of Glucose by bodycells
?In Fasting condition
--- Content provided by FirstRanker.com ---
?In between Meals?During Severe Exercises and Marathon Races
?In Patients of Diabetes mellitus
Stages And Reaction Steps
--- Content provided by FirstRanker.com ---
Of Beta Oxidation Of Fatty AcidsThree Stages Of Beta Oxidation
For
--- Content provided by FirstRanker.com ---
Fatty acid Palmitate
Stage I
Activation of Fatty acid (Acyl Chain) to
--- Content provided by FirstRanker.com ---
Acyl-CoA In Cytosol
? Palmitate to Palmitoyl-CoA
--- Content provided by FirstRanker.com ---
In Cytosol
Stage II
--- Content provided by FirstRanker.com ---
Translocation of Activated Fatty acidFrom Cytosol into Mitochondrial
Matrix
--- Content provided by FirstRanker.com ---
Through The Role of Carnitine
(Carnitine Shuttle)
Stage I I
--- Content provided by FirstRanker.com ---
Steps of Beta Oxidation Proper
In Mitochondrial Matrix
--- Content provided by FirstRanker.com ---
?Oxidation Reaction?Hydration Reaction
?Oxidation Reaction
--- Content provided by FirstRanker.com ---
?Cleavage Reaction
Stage I
--- Content provided by FirstRanker.com ---
Activation Of Fatty acidIn Cytosol
Is a Preparative Phase
--- Content provided by FirstRanker.com ---
Site Of Fatty acid Activation? Fatty acid(Acyl Chain) is activated
in Cytosol to Acyl-CoA .
--- Content provided by FirstRanker.com ---
? A long chain Fatty acid is termed as
Acyl chain.
--- Content provided by FirstRanker.com ---
? Every Fatty acid which undergoesOxidation of Fatty acid is first
activated to Acyl-CoA.
--- Content provided by FirstRanker.com ---
? Activation of aFatty acid means:
? Linking of Acyl Chain to
--- Content provided by FirstRanker.com ---
Coenzyme A to form Acyl-CoA
with a high energy bond.
--- Content provided by FirstRanker.com ---
? During Activation ofFatty acid (Acyl Chain)
? `H' of CoA-SH (Coenzyme A) is
--- Content provided by FirstRanker.com ---
substituted by Acyl chain
? To form CoA-S Acyl, i.e Acyl-CoA an
--- Content provided by FirstRanker.com ---
activated Fatty acid.?Thus CoA is a carrier of
Acyl chain in an
--- Content provided by FirstRanker.com ---
activated fatty acid.Requirements of FA Activation
?Enzyme:
--- Content provided by FirstRanker.com ---
?Thiokinase /Acyl CoA Synthetase
?Coenzymes/Cofactor:
--- Content provided by FirstRanker.com ---
?CoA-SH?ATP
?Magnesium ions (Mg++)
--- Content provided by FirstRanker.com ---
Steps Of Fatty Acid Activation
Activation of Fatty Acid
--- Content provided by FirstRanker.com ---
?An Acyl-CoA is an
activated energetic
--- Content provided by FirstRanker.com ---
compound having high
energy bond.
Activation Of a Fatty Acid
--- Content provided by FirstRanker.com ---
Is ATP Dependent
Converts ATP to AMP
--- Content provided by FirstRanker.com ---
Hence equivalent to 2 ATPs? Thus formation of Acyl?CoA is
an expensive energetical y
--- Content provided by FirstRanker.com ---
CoezymeA (CoA-SH)Activates
Fatty Acids
--- Content provided by FirstRanker.com ---
for Beta Oxidation
Acyl-CoA Synthetase/
--- Content provided by FirstRanker.com ---
Fatty Acid Thiokinasecondenses Fatty acids with CoA,
with simultaneous hydrolysis of
--- Content provided by FirstRanker.com ---
ATP to AMP and PPi
Fatty acid Activation
? Activation of Fatty acids is esterification
--- Content provided by FirstRanker.com ---
of Fatty acid with Coenzyme A
? In presence of Acyl-CoA Synthetase
--- Content provided by FirstRanker.com ---
(Thiokinase) forming an activated Fattyacid as Acyl-CoA.
? This process is ATP-dependent, & occurs
--- Content provided by FirstRanker.com ---
in 2 steps.
? During the activation of Fatty acid
--- Content provided by FirstRanker.com ---
ATP is converted to AMP and ppi.? Two high energy bonds of ATP are
cleaved and utilized in this activation
--- Content provided by FirstRanker.com ---
which is equivalent to 2 ATPs.
? Subsequent hydrolysis of PPi from
ATP drives the reaction strongly
--- Content provided by FirstRanker.com ---
forward.
? Note the Acyl- Adenylate is an
--- Content provided by FirstRanker.com ---
intermediate in the mechanism.? There are different Acyl-CoA
Synthetase for fatty acids of
--- Content provided by FirstRanker.com ---
different chain lengths.
Activated Fatty Acid (Acyl-CoA)
--- Content provided by FirstRanker.com ---
is a High Energy Compound
Which Facilitates
--- Content provided by FirstRanker.com ---
The Second StageOf
Beta Oxidation Of Fatty Acid
--- Content provided by FirstRanker.com ---
Stage ITranslocation Of Acyl-CoA
From Cytosol
--- Content provided by FirstRanker.com ---
Into Mitochondrial Matrix
With The Help Of Carnitine
--- Content provided by FirstRanker.com ---
?-oxidation properoccurs in the
Mitochondrial matrix.
--- Content provided by FirstRanker.com ---
? CoA part of Acyl-CoA is
impermeable to inner
--- Content provided by FirstRanker.com ---
membrane of Mitochondria
? Since CoA is a complex structure.
--- Content provided by FirstRanker.com ---
? Long-chain Fatty acids cannot bedirectly translocated into the
Mitochondrial matrix.
--- Content provided by FirstRanker.com ---
? However short chain Fatty acids are
directly translocated into the
--- Content provided by FirstRanker.com ---
Mitochondrial matrix? To translocate the activated long chain
Fatty acid (Acyl-CoA) from the cytosol to
--- Content provided by FirstRanker.com ---
the mitochondrial matrix? Across the mitochondrial membrane
operates a specialized Carnitine Carrier
--- Content provided by FirstRanker.com ---
System.
What Is Carnitine?
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? Carnitine is a functional, NonProtein Nitrogenous (NPN)
substance.
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? Carnitine is biosynthesized in the
body by amino acids Lysine and
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Methionine.?
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? Long chain Acyl CoA traverses
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the inner mitochondriamembrane with a special
transport mechanism called
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Carnitine Shuttle.
Mechanism Of Carnitine
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In Transport Of Fatty Acyl CoA
From Cytosol To Mitochondrial Matrix
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? Acyl-CoA a high energy
compound cleave its high energy
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bond in the second stage.? The bond energy released is used
up for linking of Carnitine to Acyl
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chain to form Acyl-Carnitine.
? Long-chain FA are converted to
Acyl Carnitine and are then
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transported
? Acyl-CoA are reformed inside
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the inner membrane ofmitochondrial matrix.
q Acyl groups from Acyl COA is
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transferred to Carnitine to form Acyl
Carnitine catalyzed by Carnitine Acyl
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Transferase I, in the outer mitochondrialmembrane
.
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q Acylcarnitine is then shuttled across theinner mitochondrial membrane by a
Translocase enzyme.
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q The Acyl group is transferred back to CoA
of Mitochondrial pool in mitochondrial
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matrix by Carnitine Acyl Transferase I .
q Finally, Carnitine is returned to the
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cytosolic side by Protein Translocase, inexchange for an incoming Acyl Carnitine.
Points To Remember
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? Cell maintains two separate pools of
Coenzyme-A:
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?Cytosolic pool of CoA?Mitochondrial pool of CoA
?CoA is complex structure cannot
transport across Mitochondrial
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membrane
?CoA linked to Fatty acid in
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Mitochondria is different fromthat CoA used for Fatty acid
activation.
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Translocation of Palmitoyl-CoAAcross Mitochondrial
Membrane
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ATP + CoA
AMP + PPi
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palmitatepalmitoyl-CoA
Cytoplasm
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OUTER
ACS
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MITOCHONDRIALCPT-I
[1]
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[2]
MEMBRANE
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CoApalmitoyl-CoA
Intermembrane
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palmitoyl-carnitine
Space
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carnitineActivation of Palmitate to Palmitoyl CoA and conversion to Palmitoyl
Carnitine
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CPT-Ipalmitoyl-CoA
CoA
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Intermembrane Space
Palmitoyl-Carnitine
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CarnitineINNER
CAT
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[3]
MITOCHONDRIAL
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MEMBRANEMatrix
CPT-II
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Carnitine
palmitoyl-carnitine
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[4]palmitoyl-CoA
CoA
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Mitochondrial uptake via of Palmitoyl-Carnitine via the Carnitine-
Acylcarnitine Translocase (CAT)
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ATP + CoA AMP + PPiCytoplasm
palmitate
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palmitoyl-CoA
OUTER
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MITOCHONDRIALACS
CPT-I
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MEMBRANE
[1]
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[2]CoA
Intermembrane
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palmitoyl-CoA
Space
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palmitoyl-carnitineCarnitine
INNER
--- Content provided by FirstRanker.com ---
CAT
[3]
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MITOCHONDRIALMEMBRANE
CPT-II
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Matrix
carnitine
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palmitoyl-carnitine[4]
palmitoyl-CoA
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CoA
Carnitine-mediated transfer of the fattyAcyl moiety into the
mitochondrial matrix is a 3-step process:
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1. Carnitine Palmitoyl Transferase I, an enzyme on thecytosolic surface of the outer mitochondrial membrane,
transfers a fatty acid from CoA to the OH on Carnitine.
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2. An Translocase/Antiporter in the inner mitochondrialmembrane mediates exchange of Carnitine for Acylcarnitine.
3. Carnitine Palmitoyl Transferase I , an enzyme within the
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matrix, transfers the fatty acid from Carnitine to CoA.
(Carnitine exits the matrix in step 2.)
The fatty acid is now esterified to CoA in the mitochondrial
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matrix.
Stage I I
Steps of Beta Oxidation Proper/Cycle
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In Mitochondrial Matrix
?Oxidation Reaction
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?Hydration Reaction?Oxidation Reaction
?Cleavage Reaction
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Site/Occurrence Of
? Oxidation Proper
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? In the Mitochondrial Matrix ofCel s.
? After the reach of Acyl-CoA in
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Mitochondrial matrix.
Mechanism Of Reactions
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Of
Beta Oxidation Proper
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ofPalmitoyl-CoA
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Step I: Oxidation by FAD linked Acyl CoA
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DehydrogenaseStep I : Hydration by Enoyl CoA
Hydratase
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Step I I: Oxidation by NAD linked
eta Hydroxy Acyl CoA Dehydrogenase
Step IV: Thiolytic Clevage Keto Thiolase
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Palmitoylcarnitineinner mitochondrial
Carnitine
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membrane
respiratory chain
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translocasePalmitoylcarnitine
matrix side
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1.5 ATP2.5 ATP
Palmitoyl-CoA
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FADoxidation
FADH2
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hydration
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H2O-Oxidation of
recycle
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NAD+
Palmitoyl CoA
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oxidation6 times
NADH
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cleavage
CoA
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CH3-(CH)12-C-S-CoA + Acetyl CoACitric
O
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acid
cycle
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2 CO2? Strategy of First 3 reactions of Beta
Oxidation proper is to
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? Create a Carbonyl group (C=O) on
the -Carbon atom (CH2) of a Fatty
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acid.? This weakens the bond between
and Carbon atoms of Fatty acid.
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? Fourth reaction cleaves the
"-Keto ester" in a reverse
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Claisen condensation
reaction.
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? Products of Each turn/cycle ofbeta oxidation proper are :
?Acetyl-CoA
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?Acyl-CoA with two carbonsshorter
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Step 1
Role Of
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Acyl-CoA DehydrogenaseTo Bring
Oxidation of the C-C bond
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of Fatty acid
Acyl CoA Dehydrogenase is a
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FAD linked Enzyme(Flavoprotein)
? Acyl CoA Dehydrogenase catalyzes
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Oxidation reaction? Where there is a removal of
Hydrogen from alpha and beta
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carbon atoms of Acyl-CoA.
? There forms a double bond
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between C -C / C2 and C3 ofFatty Acid.
? The product of this oxidation
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reaction is - Unsaturated Acyl
CoA /Trans Enoyl CoA.
? Coenzyme FAD is the temporary
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hydrogen acceptor in this oxidation
reaction .
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? The reduced FADH2 is generated byoxidation reaction of Acyl CoA
Dehydrogenase.
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? FADH2 is then reoxidized, after its enter
into Electron Transport Chain
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? Mechanism of Acyl CoADehydrogenase involves :
?Proton Abstraction/Removes
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Hydrogen
?Double bond formation
?Hydride removal by FAD
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?Generation of reduced FADH2--- Content provided by FirstRanker.com ---
? FADH2 is oxidized by entering into
ETC.
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? Electrons from FADH2 are passed toElectron transport chain
components,
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? Coupled with phosphorylation to
generate 1.5 ATP
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(By Oxidative Phosphorylation).Acyl-CoA Dehydrogenase
? There are different Acyl-CoA
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Dehydrogenases :
?Short Chain Fatty acids (4-6 C),
?Medium Chain Fatty Acids (6-10 C),
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?Long (12-18 C) and very long (22 andmore)chain Fatty acids.
Inhibitor Of
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Acyl CoA Dehydrogenase?Acyl CoA Dehydrogenase is
inhibited by a Hypoglycin
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(from Akee fruit)
Step 2
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Role OfEnoyl CoA Hydratase
To add water across the double bond
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C = C of Trans-Enoyl-CoA
Saturate the double bond of Enoyl-CoA
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Generate Hydroxyl group at beta carbon?Enoyl-CoA Hydratase catalyzes
stereospecific hydration of the trans
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double bond?It adds water across the double bond
at C2 and C3 of Trans Enoyl CoA
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?This hydration reaction generates
Hydroxyl (OH) group at beta
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carbon atom of FA?Converts Trans-Enoyl-CoA to
L -Hydroxyacyl-CoA
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Step 3
Role Of
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Hydroxyacyl-CoA Dehydrogenase
To Oxidizes the -Hydroxyl Group of
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-Hydroxyacyl-CoAAnd
Transform it into
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-Ketoacyl-CoA
? -Hydroxyacyl-CoA Dehydrogenase is
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NAD+ dependent
? It catalyzes specific oxidation of the
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Hydroxyl group in the b position (C3) toform a ketone group.
? NAD+ is the temporary electron acceptor
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for this step which generates reduced
form NADH+H+
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? The oxidation of-Hydroxyacyl CoA produces a
product - Ketoacyl-CoA.
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Step 4
Role Of b- Ketothiolase
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/Thiolase
Catalyzes Thiolytic cleavage of the
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two carbon fragmentby splitting the
bond between and carbons
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? An enzyme -Keto Thiolase attacks
the -carbonyl group of -Ketoacyl-
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CoA.
? This results in the cleavage of the
C-C bond.
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? Releases Acetyl-CoA(2C) and an Acyl-
CoA (-2carbons shorter ).
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Repetitions Of 4 Steps Of
Beta Oxidation Proper
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? The b-oxidation proper pathwayis cyclic.
? 4 Steps of Beta Oxidation proper
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are repeated
? Til whole chain of Fatty acid is
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oxidized completely.? The product, 2 carbons
shorter Acyl -CoA,
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? Is the input to another
round/turn of the beta
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oxidation proper pathway.? Acyl CoA molecule released at end of
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Beta Oxidation? Is the substrate for the next round of
oxidation starting with Acyl CoA
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Dehydrogenase.
? Repetition continues until all the carbon
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atoms of the original Fatty acyl CoA areconverted to Acetyl CoA.
The shortened Acyl
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CoA then undergoes
another cycle of beta
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oxidationThe number of beta
oxidation cycles:
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n/2-1, where n ? thenumber of carbon atoms
Products Of Each Turn
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OfBeta Oxidation Proper
? Each turn/cycle of oxidation proper
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generates one molecule each of:
?FADH2
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?NADH+H+?Acetyl CoA
?Fatty Acyl CoA ( with 2 carbons shorter each round)
Steps Of
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-Oxidation Properof Fatty Acids Continues
With
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A Repeated Sequence
of 4 Reactions
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TilA Long Fatty Acyl Chain Is
Completely Oxidized
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?For an oxidation of Palmitic
acid through beta oxidation
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? 7 turns/cycles of betaoxidation proper steps occur.
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Beta OxidationFates of the products
of
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-oxidation of Fatty Acid
? NADH+H+ and FADH2 - are
reoxidized in ETC to generate ATP
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? Acetyl CoA - Enters the Citric acid
cycle(TCA cycle) for its complete
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oxidation.? Acyl CoA ? Undergoes the next
turn/cycle of oxidation proper.
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Complete Oxidation Of Fatty Acids
Fatty Acid
Oxidation
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Acetyl CoA +ATP
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TCA CycleCO2 +H2O and ATP
? Fatty acid is activated and oxidized via
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Beta Oxidation in specific number of
cycles depending upon chain length.
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? Acetyl CoA an end product of Betaoxidation of Fatty acid
? Is further completely oxidized via
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TCA cycle.
1
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Palmitoylcarnitine
inner mitochondrial
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Carnitinemembrane
respiratory chain
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translocase
Palmitoylcarnitine
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matrix side1.5 ATP2.5 ATP
Palmitoyl-CoA
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FAD
oxidation
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FADH2Figure 4.
hydration
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H2O
Processing and
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NAD+-oxidation of
recycle
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oxidation
Palmitoyl CoA
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6 timesNADH
cleavage
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CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
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CitricO
acid
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cycle
2 CO2
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-Oxidation
Overal Flow
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CAPILLARYLipoproteins
(Chylomicrons
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L [2]
FABP
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MITOCHONDRIONP
or VLDL)
--- Content provided by FirstRanker.com ---
FA
L
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acetyl-CoATCA
A
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[7]
[3]
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cycle[4] C
FA
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FA
-oxidation
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S[6]
FA
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FA
albumin
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acyl-CoAacyl-CoA
FABP
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FABP
FA
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[5]carnitine
CYTOPLASM
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transporter
[1]
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fromfat
cel membrane
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cel
FA = fatty acid
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LPL = lipoprotein lipaseFABP = fatty acid binding protein
ACS = acyl CoA synthetase
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Figure 2. Overview of fatty acid degradation
Energetics Of Beta oxidation
Of Palmitate
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? Oxidation of Palmitic Acid C16
Number of turns of fatty acid
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spiral = 8-1 = 7 Cycles of betaoxidation proper.
? Generates 8 Acetyl CoA
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During Electron Transport andOxidative Phosphorylation
Each FADH2 yield 1.5 ATP
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and NADH 2.5 ATP
Energetics of Fatty Acid Beta Oxidation
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e.g. Palmitic (16C):1.-oxidation of Palmitic acid will be repeated in 7
cycles producing 8 molecules of Acetyl COA.
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2.In each cycle 1 FADH2 and 1 NADH+H+ is produced
and will be transported to the respiratory chain/ETC.
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? FADH2 1.5 ATP? NADH + H+ 2.5 ATP
? Thus Each cycle of -oxidation 04 ATP
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? So 7 cycles of -oxidation 4 x 7 = 28 ATP
1 Acetyl CoA yields 10
ATPs
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via
TCA Cycle
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? Review ATP Generation ?TCA/ Citric AcidCycle which start with Acetyl CoA
? Step
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ATP produced
? Step 4 (NADH+H to ETC)
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2.5 ATP? Step 6 (NADH+H to E.T.C.) 2.5 ATP
? Step 10 (NADH+H to ETC) 2.5 ATP
--- Content provided by FirstRanker.com ---
? Step 8 (FADH2 to E.T.C.)
1.5 ATP
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? 1 GTP01 ATP
? NET per turn of TCA Cycle 10 ATP
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1 ATP converted to AMPduring activation of
Palmitic acid to Palmitoyl-CoA
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is equivalent to 2ATPs utilized
3. Each Acetyl COA which is oxidized
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completely in citric cycle/TCA cycle gives 10ATP
4. Hence 8 Acetyl CoA via TCA cycle (8 x 10 =
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80 ATP)
5. 2 ATP are utilized in the activation of Fatty
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acid6. Energy gain = Energy produced - Energy
utilized
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7. 28 ATP + 80 ATP - 2 ATP = 106 ATP
Thus On Complete Oxidation of
One molecule of Palmitate
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106 molecules of ATP
are generated
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ATP Generation from Palmitate OxidationNet yield of ATP per one oxidized Palmitate
Palmitate (C15H31COOH) - 7 cycles ? n/2-1
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Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O
--- Content provided by FirstRanker.com ---
8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+ATP generated
8 Acetyl CoA(TCA)
--- Content provided by FirstRanker.com ---
10x8=807 FADH2
7x1.5=10.5
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7 NADH
7x2.5=17.5
--- Content provided by FirstRanker.com ---
108 ATPATP expended to activate Palmitate -2 ATP
Net yield of ATPs with Palmitate Oxidation: 106 ATP
--- Content provided by FirstRanker.com ---
Total End ProductsOf
Beta Oxidation
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Of
1 molecule of a Palmitic Acid
--- Content provided by FirstRanker.com ---
Palmitic acid
With 7 Turns of
--- Content provided by FirstRanker.com ---
Beta Oxidation ProperGenerates
8 Molecules Of Acetyl-CoA
--- Content provided by FirstRanker.com ---
7 FADH2+7 NADH+H+
-Oxidation Proper of Acyl-CoA
--- Content provided by FirstRanker.com ---
Summary of one round/turn/cycle of the
b-oxidation pathway:
--- Content provided by FirstRanker.com ---
Fatty Acyl-CoA + FAD + NAD+ + HS-CoA+Acetyl-CoA
Fatty Acyl-CoA (2 C less) + FADH2 + NADH + H+
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Stoichiometry for
--- Content provided by FirstRanker.com ---
Palmitic Acid Oxidation
b F
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-O atxi ty
da acyl
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tion CoA
of
--- Content provided by FirstRanker.com ---
Saturated fatty acidsRegulation Of Beta Oxidation
Of Fatty Acids
--- Content provided by FirstRanker.com ---
?The Lipolysis andOxidation of Fatty acids
are well regulated by
--- Content provided by FirstRanker.com ---
Hormonal influence.Insulin In Wel Fed Condition
? Insulin inhibits Lipolysis of Adipose
--- Content provided by FirstRanker.com ---
Fat (TAG) and mobilization of FreeFatty acids.
? Insulin decreases Oxidation of
--- Content provided by FirstRanker.com ---
Fatty acids.
Glucagon In Emergency Condition
--- Content provided by FirstRanker.com ---
? When Cellular or Blood Glucoselowers down there is secretion of
Glucagon.
--- Content provided by FirstRanker.com ---
? Glucagon and Epinephrine
stimulates Lipolysis in emergency
--- Content provided by FirstRanker.com ---
condition.? Glucagon stimulates the Enzyme
Hormone sensitive Lipase and
--- Content provided by FirstRanker.com ---
hydrolyzes depot Fat(TAG).? Glucagon mobilizes Free fatty
acids out into blood circulation
--- Content provided by FirstRanker.com ---
? Increases Oxidation of Fatty
acids.
--- Content provided by FirstRanker.com ---
Regulation OfBeta Oxidation Of Fatty Acid
At Two Levels
--- Content provided by FirstRanker.com ---
? Carnitine Shuttle
? Beta Oxidation Proper
Transport of Fatty Acyl CoA
--- Content provided by FirstRanker.com ---
fromCytosol
into Via Carnitine Shuttle
--- Content provided by FirstRanker.com ---
Mitochondrial Matrix
Is a Rate-limiting step
--- Content provided by FirstRanker.com ---
Malonyl-CoARegulates Beta Oxidation
At Carnitine Transport
--- Content provided by FirstRanker.com ---
Level
Malonyl-CoA Is an Inhibitor Of
--- Content provided by FirstRanker.com ---
Carnitine Acyl Transferase IMalonyl-CoA is produced from Acetyl-CoA by the enzyme
Acetyl-CoA Carboxylase during Fatty acid biosynthesis.
Malonyl-CoA (which is a precursor for fatty acid synthesis)
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inhibits Carnitine Palmitoyl Transferase I.
This Control of Fatty acid oxidation is exerted mainly at the
step of Fatty acid entry into mitochondria.
--- Content provided by FirstRanker.com ---
Acyl-CoA Dehydrogenase is
Regulatory or key Enzyme
--- Content provided by FirstRanker.com ---
ofBeta Oxidation Of Fatty Acids
Significance Of Beta oxidation
--- Content provided by FirstRanker.com ---
of a Fatty acid?Beta oxidation cycles
helps in cleaving and
--- Content provided by FirstRanker.com ---
shortening of a long
chain Fatty acid
? Oxidation of Beta carbon
--- Content provided by FirstRanker.com ---
atom of a Fatty acid
transforms the stronger
--- Content provided by FirstRanker.com ---
bond between alpha andbeta carbon atom to a
weaker bond.
--- Content provided by FirstRanker.com ---
? Transformation to a weaker bond
helps in easy cleavage between
--- Content provided by FirstRanker.com ---
alpha and beta carbon? During oxidation there is
dehydrogenation of beta carbon
--- Content provided by FirstRanker.com ---
atom (CH2 to C=O)
? The Hydrogen atoms removed during
beta oxidation are
--- Content provided by FirstRanker.com ---
? Temporarily accepted by the oxidized
coenzymes (FAD and NAD+) to form
--- Content provided by FirstRanker.com ---
reduced coenzymes? Reduced coenzymes then final y enter
ETC and get reoxidized
--- Content provided by FirstRanker.com ---
? The byproduct of ETC is ATP
? Thus Beta oxidation of
--- Content provided by FirstRanker.com ---
Fatty acid? Metabolizes a long chain
fatty acid with liberation of
--- Content provided by FirstRanker.com ---
chemical form of energy
ATP for cel ular activities.
Summary of -Oxidation
--- Content provided by FirstRanker.com ---
Repetition of the -Oxidation Cycle yields a succession of
Acetate units
--- Content provided by FirstRanker.com ---
? Palmitic acid yields eight Acetyl-CoAs? Complete -oxidation of one Palmitic acid yields
106 molecules of ATP
--- Content provided by FirstRanker.com ---
? Large energy yield is consequence of the highlyreduced state of the carbon in fatty acids
? This makes fatty acid the fuel of choice for
--- Content provided by FirstRanker.com ---
migratory birds and many other animals
Disorders OF Beta Oxidation
--- Content provided by FirstRanker.com ---
Of Fatty AcidsDeficiencies of Carnitine
OR
--- Content provided by FirstRanker.com ---
Carnitine TransferaseOR
Translocase Activity
--- Content provided by FirstRanker.com ---
Are
Related to Disease State
--- Content provided by FirstRanker.com ---
Carnitine Shuttle Defects?Affects the normal
function of Muscles,
--- Content provided by FirstRanker.com ---
Kidney, and Heart.
? Symptoms include Muscle
cramping, during exercise, severe
--- Content provided by FirstRanker.com ---
weakness and death.
? Muscle weakness occurs since
--- Content provided by FirstRanker.com ---
they are related with Fatty acidoxidation for long term energy
source.
--- Content provided by FirstRanker.com ---
? Note people with the Carnitine
Transporter Defect
--- Content provided by FirstRanker.com ---
?Should be supplemented with a dietwith medium chain fatty acids
?Since the MCFAs do not require
--- Content provided by FirstRanker.com ---
Carnitine shuttle to enter
Mitochondria.
Sudden Infant Death Syndrome
--- Content provided by FirstRanker.com ---
(SIDS)
SIDS
--- Content provided by FirstRanker.com ---
? SIDS is a congenital rare disorderwith an incidence of 1 in 10,000
births.
--- Content provided by FirstRanker.com ---
? Cause: Due to the deficiency of
Enzyme Acyl-CoA Dehydrogenase a
--- Content provided by FirstRanker.com ---
regulatory enzyme of Oxidationof Fatty acid.
? Consequences Of SIDS
--- Content provided by FirstRanker.com ---
? Deficiency of Acyl-CoA Dehydrogenase? Blocks the Oxidation of Fatty acid.
? Stops liberation and supply of energy in
the form of ATPs in fasting condition
--- Content provided by FirstRanker.com ---
? Leads to unexpected death of an infant.
Symptoms in defective Beta Oxidation of Fatty
--- Content provided by FirstRanker.com ---
acids include:wHypoglycemia
wLow Ketone body production during
--- Content provided by FirstRanker.com ---
fastingwFatty Liver
wHeart and/or Skeletal muscle defects
wComplications of pregnancy
--- Content provided by FirstRanker.com ---
wSudden infant death (SID).? Hereditary deficiency of Medium
Chain Acyl-CoA Dehydrogenase
--- Content provided by FirstRanker.com ---
(MCAD),? The most common genetic
disease relating to fatty acid
--- Content provided by FirstRanker.com ---
catabolism, has been linked to
SIDS.
--- Content provided by FirstRanker.com ---
Jamaican Vomiting Sickness? Jamaican Vomiting Syndrome
--- Content provided by FirstRanker.com ---
is due to ingestion of unripeAckee fruit by people in
Jamaica
--- Content provided by FirstRanker.com ---
(Jamaica-Country of Caribbean)
Ackee Fruit
? The Ackee fruit is rich in
--- Content provided by FirstRanker.com ---
Hypoglycin ?A
? Hypoglycin is an inhibitor of
--- Content provided by FirstRanker.com ---
regulatory Enzyme OxidationProper Acyl-CoA Dehydrogenase.
? The Jamaican Vomiting Disease leads
--- Content provided by FirstRanker.com ---
to complications characterized by :
?Severe Vomiting
?Hypoglycemia
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?Convulsions?Coma
?Death
Beta Oxidation
--- Content provided by FirstRanker.com ---
OfOdd Chain Saturated Fatty Acids
-OXIDATION
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OF
ODD-CHAIN FATTY ACIDS
?Odd chain carbon Fatty
--- Content provided by FirstRanker.com ---
acids are less common in
human body.
--- Content provided by FirstRanker.com ---
?Formed by some bacteriain the stomachs of
ruminants and the human
--- Content provided by FirstRanker.com ---
colon.
? -oxidation of odd chain Fatty
--- Content provided by FirstRanker.com ---
acid occurs same as evenchain Fatty acid oxidation
? Until the final Thiolase
--- Content provided by FirstRanker.com ---
cleavage
? Which results in a 3 Carbon
--- Content provided by FirstRanker.com ---
Acyl-CoA /Propionyl-CoA? Odd-carbon Fatty acids are
metabolized same as even carbon
--- Content provided by FirstRanker.com ---
chain Fatty acid via steps ofoxidation, releasing Acetyl CoA (2C)
in every turn.
--- Content provided by FirstRanker.com ---
? In the last turn of oxidation
proper of odd chain fatty acid
--- Content provided by FirstRanker.com ---
? Releases last three-C fragment as
Propionyl-CoA (3 C).
End Products Of Odd Chain Fatty Acid
--- Content provided by FirstRanker.com ---
Oxidation
? End products of b-oxidation of
--- Content provided by FirstRanker.com ---
an odd-number Fatty acid is :?Acetyl-CoA(C2)
?Propionyl-CoA(C3)
Fate Of Acetyl-CoA
--- Content provided by FirstRanker.com ---
? Acetyl CoA released from beta
oxidation of odd chain fatty
--- Content provided by FirstRanker.com ---
acid? Enter in TCA cycle and get
completely oxidized.
--- Content provided by FirstRanker.com ---
Fate Of Propionyl-CoA
Metabolism Of Propionyl CoA
Propionyl CoA
--- Content provided by FirstRanker.com ---
An End Product Of Odd Chain
Fatty Acid
--- Content provided by FirstRanker.com ---
Is Converted intoSuccinyl CoA
A TCA intermediate
--- Content provided by FirstRanker.com ---
? Metabolism of Propionyl-CoA? The Propionyl-CoA is
converted to Succinyl-CoA.
--- Content provided by FirstRanker.com ---
? Which is an intermediate of
TCA/Citric acid cycle
? Propionyl CoA metabolism is
--- Content provided by FirstRanker.com ---
dependent on Vitamin B
complex members:
--- Content provided by FirstRanker.com ---
?Biotin?Vitamin B12
? Special set of 3 Enzymes are
--- Content provided by FirstRanker.com ---
required to further oxidizePropionyl-CoA to Succinyl -CoA.
? Final Product Succinyl-CoA enters
--- Content provided by FirstRanker.com ---
TCA cycle and get metabolized.
? Three Enzymes convert Propionyl-
--- Content provided by FirstRanker.com ---
CoA to Succinyl-CoA:
1. Carboxylase
2. Racemase /Epimerase
--- Content provided by FirstRanker.com ---
3. MutaseStep1
--- Content provided by FirstRanker.com ---
? Propionyl CoA is Carboxylated to yieldD Methylmalonyl CoA.
? Enzyme: Propionyl CoA Carboxylase
? Coenzyme: Cyto Biotin
? An ATP is required
--- Content provided by FirstRanker.com ---
Step2
? The D Methylmalonyl CoA
--- Content provided by FirstRanker.com ---
is racemized to the
L Methylmalonyl CoA.
--- Content provided by FirstRanker.com ---
? Enzyme: Methylmalonyl-CoARacemase/ Epimerase
--- Content provided by FirstRanker.com ---
Step 3? L Methylmalonyl CoA is converted
into Succinyl CoA by an
--- Content provided by FirstRanker.com ---
intramolecular rearrangement
? Enzyme: Methylmalonyl CoA
--- Content provided by FirstRanker.com ---
Mutase? Coenzyme of Vitamin B12 :Deoxy
Adenosyl Cobalamin
--- Content provided by FirstRanker.com ---
Fates Of Succinyl CoA? Succinyl CoA
? Enters TCA cycle and get metabolized
--- Content provided by FirstRanker.com ---
? Serve as Glucogenic precursor for Glucosebiosynthesis in emergency condition
? Used as a precursor for Heme biosynthesis
--- Content provided by FirstRanker.com ---
? Involves in Thiophorase reaction of Ketolysis.Oxidation of Odd-chain Fatty Acids
--- Content provided by FirstRanker.com ---
Conversion of Propionyl-CoA to Succinyl-CoADefects In Propionyl CoA Metabolism
? Deficiency of Enzyme Propionyl-CoA
--- Content provided by FirstRanker.com ---
Carboxylase will block themetabolism of Propionyl-CoA.
? Accumulates Propionyl-CoA in blood
--- Content provided by FirstRanker.com ---
leading to Propionicacidemia.
? Deficiency of Vitamin B Complex
--- Content provided by FirstRanker.com ---
members affects Propionyl CoAmetabolism to Succinyl ?CoA.
? Vitamin B12 deficiency blocks the
--- Content provided by FirstRanker.com ---
Mutase reaction
? Accumulates L-Methyl Malonyl-
--- Content provided by FirstRanker.com ---
CoA leading to MethylMalonylaciduria.
Alpha Oxidation Of Fatty Acid
--- Content provided by FirstRanker.com ---
OROxidation Of
Branched-Chain Fatty Acid
--- Content provided by FirstRanker.com ---
OR
Phytanic Acid Oxidation
--- Content provided by FirstRanker.com ---
? The source of Phytanic acid inhuman body is through
ingestion of green leafy
--- Content provided by FirstRanker.com ---
vegetables.
? Phytanic acid is a breakdown
--- Content provided by FirstRanker.com ---
product of plant chlorophyl .Why Phytanic Acid
Does Not Initiate With
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Beta Oxidation Process?? Phytanic acid is a Branched
chain FA.
--- Content provided by FirstRanker.com ---
? Has Methyl branches at odd
-number carbons.
--- Content provided by FirstRanker.com ---
? They are not goodsubstrates for -oxidation.
? The branched chain Phytanic
--- Content provided by FirstRanker.com ---
acid contains Methyl (CH3)group at Carbon atom.
? Hence it cannot get oxidized
--- Content provided by FirstRanker.com ---
initial y via oxidation
pathway
--- Content provided by FirstRanker.com ---
?Thus initially Phytanic acidfol ows Oxidation
?Modify Phytanic acid to
--- Content provided by FirstRanker.com ---
Pristanic acid and
?Further present it for
--- Content provided by FirstRanker.com ---
Beta Oxidation process.Occurrence Of Alpha
Oxidation Of Phytanic Acid
--- Content provided by FirstRanker.com ---
Predominantly Alpha OxidationOf Phytanic Acid
Takes Place in
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Endoplasmic Reticulum
of Brain Cel s
--- Content provided by FirstRanker.com ---
Also In PeroxisomesMechanism Of Alpha
Oxidation Of Phytanic Acid
--- Content provided by FirstRanker.com ---
? Phytanic acid 3,7,11,15-Tetramethyl Hexadecanoic
acid
--- Content provided by FirstRanker.com ---
? Alpha oxidation removes the
Methyl groups at beta carbon.
--- Content provided by FirstRanker.com ---
? Later making the Fatty acidready for beta oxidation
process.
--- Content provided by FirstRanker.com ---
? During Oxidation there occurs:
? Hydroxylation at Carbon in
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presence of Enzyme Hydroxylase or
Monoxygenase .
--- Content provided by FirstRanker.com ---
? This reaction is Vitamin C dependentforming Hydroxy Acyl-CoA.
? Hydroxy Acyl-CoA is then
--- Content provided by FirstRanker.com ---
oxidized to Keto Acyl-CoA.? The Ketonic group at Carbon
atom is decarboxylated
--- Content provided by FirstRanker.com ---
? Yielding CO2 molecule and a Fatty
acid with one Carbon atom less.
--- Content provided by FirstRanker.com ---
? Phytanic acid on alpha oxidation isconverted to Pristanic acid
? Which is further metabolized via
--- Content provided by FirstRanker.com ---
beta oxidation process to
generate Propionyl-CoA.
Products of Phytanic Acid Oxidation
--- Content provided by FirstRanker.com ---
? Alpha oxidation of Phytanic acid
Generates
--- Content provided by FirstRanker.com ---
?Acetyl-CoA?Propionyl-CoA
?Isobutryl-CoA
--- Content provided by FirstRanker.com ---
Refsums Disease
Disorders Associated
With
--- Content provided by FirstRanker.com ---
Defective Oxidation
Of Phytanic Acid
--- Content provided by FirstRanker.com ---
?Refsums disease is a rarebut severe neurological
disorder.
--- Content provided by FirstRanker.com ---
?Caused due to defect in
Oxidation of Phytanic
--- Content provided by FirstRanker.com ---
acidThe Enzyme Defects
? Deficiency of Enzyme Phytanic
--- Content provided by FirstRanker.com ---
acid Oxidase/ Phytanol-CoADioxygenase leads to Refsum's
disease.
--- Content provided by FirstRanker.com ---
? Biochemical Consequence Of Refsums
disease Is:
--- Content provided by FirstRanker.com ---
? No Oxidation of Phytanic acid? Accumulation of Phytanic acid in
Brain cel s and Other Tissues
--- Content provided by FirstRanker.com ---
? Dysfunction of Brain? Manifesting Neurological disorder
? Management Of Refsums
disease is :
--- Content provided by FirstRanker.com ---
? Avoid eating diet containing
Phytol /Phytanic acid.
--- Content provided by FirstRanker.com ---
Omega Oxidation Of Fatty Acids?Omega Oxidation of Fatty
acid is:
--- Content provided by FirstRanker.com ---
?Oxidation of Omega Carbon
atom (CH3) of a Fatty acid.
--- Content provided by FirstRanker.com ---
When Does Omega OxidationOf Fatty Acid Occurs?
? Omega Oxidation takes
--- Content provided by FirstRanker.com ---
place when there is defectin Oxidation of fatty acid.
?During Oxidation of
--- Content provided by FirstRanker.com ---
Fatty acid
? Carbon atom (CH3)
--- Content provided by FirstRanker.com ---
of a Fatty acid istransformed to -COOH
? The omega oxidation forms
--- Content provided by FirstRanker.com ---
Dicarboxylic acid? Which further undergo oxidation
? Form more short Dicarboxylic
--- Content provided by FirstRanker.com ---
acids Adipic acid and Succinic acid? Which are more polar excreted
out in Urine.
--- Content provided by FirstRanker.com ---
-Oxidation of Fatty acids
Occur in the
--- Content provided by FirstRanker.com ---
Endoplasmic Reticulumof Liver Cells
Mechanism Of Oxidation
--- Content provided by FirstRanker.com ---
? Oxidation of Fattyacid is a minor
alternative oxidative
--- Content provided by FirstRanker.com ---
Pathway.
? Omega Oxidation of a Fatty
--- Content provided by FirstRanker.com ---
acid takes place with:?Hydroxylation Reaction
?Oxidation Reaction
--- Content provided by FirstRanker.com ---
=Omega,the
lastletterinthe
Greekalphabet
? In Oxidation of Fatty acid there occurs
--- Content provided by FirstRanker.com ---
Hydroxylation at Carbon atom
? Converting into Primary terminal
--- Content provided by FirstRanker.com ---
Alcohol (-CH2OH) group.? This reaction is catalyzed by NADPH+H+
dependent Cytochrome P450 system
--- Content provided by FirstRanker.com ---
? Next the primary terminal Alcohol group
is oxidized to form -COOH group .
--- Content provided by FirstRanker.com ---
? Further the Dicarboxylic acidgenerated through Omega
Oxidation undergoes beta
--- Content provided by FirstRanker.com ---
oxidation
? To produce short chain
--- Content provided by FirstRanker.com ---
Dicarboxylic acids as Adipic acidand Succinic acid
? Which are polar and excreted
--- Content provided by FirstRanker.com ---
out through Urine.
Significance Of Omega Oxidation
? Omega Oxidation transforms a
--- Content provided by FirstRanker.com ---
non polar Fatty acid to polar
Dicarboxylic fatty acid.
--- Content provided by FirstRanker.com ---
? Omega Oxidation of fatty acidfacilitates excretion of
accumulated fatty acids due to
--- Content provided by FirstRanker.com ---
defective normal Oxidation in
the cel s.
--- Content provided by FirstRanker.com ---
Peroxisomal Oxidation OfFatty Acids
OXIDATION OF FATTY ACIDS IN PEROXISOMES
--- Content provided by FirstRanker.com ---
? Peroxisomes ? Cell organellescontaining Enzymes Peroxidase and
Catalase
--- Content provided by FirstRanker.com ---
? These Enzymes catalyzes the
dismutation of Hydrogen peroxide
--- Content provided by FirstRanker.com ---
into water and molecular oxygenWhen ? Why? How?
Does
--- Content provided by FirstRanker.com ---
Peroxisomal Oxidation
OF
--- Content provided by FirstRanker.com ---
Fatty Acid Occurs?vb-Oxidation of very long-chain
fatty acids(>C22) occurs within
--- Content provided by FirstRanker.com ---
Peroxisomes initial yv Later undergoes
Mitochondrial Oxidation .
--- Content provided by FirstRanker.com ---
? Carnitine is involved in transferof Very long Chain Fatty acids
(VLCFAS >C22) into and out of
--- Content provided by FirstRanker.com ---
Peroxisomes.
? Peroxisomal Fatty acid oxidation
--- Content provided by FirstRanker.com ---
is induced by a high Fat diet withVLCFAs.
? To shortens the VLCFAs into
--- Content provided by FirstRanker.com ---
LCFAs
? Which are further degraded by
--- Content provided by FirstRanker.com ---
Beta oxidation process.Peroxisomal -Oxidation
--- Content provided by FirstRanker.com ---
? Similar to Mitochondrial -
oxidation,
--- Content provided by FirstRanker.com ---
? Initial double bond formation
is catalyzed by Flavoprotein
--- Content provided by FirstRanker.com ---
Acyl-CoA OxidaseAcyl CoA Oxidase?FAD transfers electrons to
--- Content provided by FirstRanker.com ---
O2 to yield H2O2.? Coenzyme FAD is e- acceptor
for Peroxisomal Acyl-CoA
--- Content provided by FirstRanker.com ---
Oxidase, which catalyzes the
1st oxidative step of the
--- Content provided by FirstRanker.com ---
pathway.? FADH2 generated at this step
instead of transferring the high-
--- Content provided by FirstRanker.com ---
energy electrons to ETC, asoccurs in Mitochondrial beta-
oxidation.
--- Content provided by FirstRanker.com ---
? Electrons of FADH2 directly go
to O2 at reaction level to
--- Content provided by FirstRanker.com ---
generate H2O2 in Peroxisomes.? Thus FADH2 generated in
Peroxisomes by Fatty acid oxidation
--- Content provided by FirstRanker.com ---
do not enter ETC to liberate ATPs.
? Instead the peroxisome, FADH2
--- Content provided by FirstRanker.com ---
generated by fatty acid oxidation byAcyl CoA Oxidase is reoxidized
producing Hydrogen peroxide.
--- Content provided by FirstRanker.com ---
FADH2 + O2 FAD + H2O2The Peroxisomal enzyme Catalase
degrades H2O2:
--- Content provided by FirstRanker.com ---
2 H2O2 2 H2O + O2
These reactions produce No ATP.
? Once Very Long Chain Fatty acids
--- Content provided by FirstRanker.com ---
are reduced in length within the
Peroxisomes
--- Content provided by FirstRanker.com ---
? They may shift to theMitochondrial beta oxidation for
further catabolism of fatty acids.
--- Content provided by FirstRanker.com ---
?Fewer ATPs resultfrom Peroxisomal
oxidation of VLCFAs.
--- Content provided by FirstRanker.com ---
?Steps of Peroxisomal
Oxidation of Fatty acid
--- Content provided by FirstRanker.com ---
does not generate ATPs?Instead the energy
dissipated in the form of
--- Content provided by FirstRanker.com ---
heat.
? Many drugs commercially available
in market for reducing obesity
--- Content provided by FirstRanker.com ---
? Stimulate Peroxisomal beta
oxidation
--- Content provided by FirstRanker.com ---
? Where the Fatty acids are oxidizedwithout much liberation of calories
(ATPs).
--- Content provided by FirstRanker.com ---
? Peroxisomal Oxidation of Fatty
acid efficiently takes place in:
--- Content provided by FirstRanker.com ---
?Obese persons?Persons taking Hypolipidemic
drugs(Clofibrate).
--- Content provided by FirstRanker.com ---
Zel wegers Syndrome
OR
--- Content provided by FirstRanker.com ---
Cerebrohepatorenal SyndromePeroxisomal Disorder
--- Content provided by FirstRanker.com ---
? ZellwegerSyndrome
? Cerebro-Hepato-
--- Content provided by FirstRanker.com ---
Renal Syndrome
Biochemical Causes
?Rare genetic autosomal
--- Content provided by FirstRanker.com ---
recessive disorder.
?Characterized by
--- Content provided by FirstRanker.com ---
absence of functionalPeroxisomes.
?Gene mutations in
--- Content provided by FirstRanker.com ---
PEX Genes leads to
Zel wegers Syndrome.
Biochemical Alterations
--- Content provided by FirstRanker.com ---
? No oxidation of very long
chain Fatty acids and
--- Content provided by FirstRanker.com ---
branched chain fatty acidsin Peroxisomes
?Accumulation of large
--- Content provided by FirstRanker.com ---
abnormal amounts of VLCFAs
in Peroxisomes of tissues.
--- Content provided by FirstRanker.com ---
?No normal function ofPeroxisomes.
? Progressive degeneration of
--- Content provided by FirstRanker.com ---
Brain/Liver/Kidney, withdeath ~6 month after onset.
Signs and Symptoms
--- Content provided by FirstRanker.com ---
? Defect in normal function of multiple organ
system.
--- Content provided by FirstRanker.com ---
? Impaired neuronal migration, positioning andbrain development.
? Hypomyelination affecting nerve impulse
--- Content provided by FirstRanker.com ---
transmission.
? Hepatomegaly
? Renal Cysts
--- Content provided by FirstRanker.com ---
? Typical Dysmorphic facies.Diagnosis
--- Content provided by FirstRanker.com ---
?Detection of Increasedlevels of Serum Very
Long Chain Fatty Acids-
--- Content provided by FirstRanker.com ---
VLCFAs
Oxidation Of Unsaturated
Fatty Acids
--- Content provided by FirstRanker.com ---
? PUFAs having double bonds in their
structure are unstable.
--- Content provided by FirstRanker.com ---
? The double bonds are hydrolyzed andmetabolized faster than saturated
bonds.
--- Content provided by FirstRanker.com ---
? Thus dietary intake of PUFA get
readily metabolized
--- Content provided by FirstRanker.com ---
? Which reduces risk ofAtherosclerosis.
Mechanism Of Oxidation
--- Content provided by FirstRanker.com ---
Of Unsaturated FattyAcids
? Initial and later the Oxidation
--- Content provided by FirstRanker.com ---
of PUFAs is by
? Similar steps of Oxidation
--- Content provided by FirstRanker.com ---
in the parts, of saturatedbonds.
? The double bonds of UFAs are cleaved
--- Content provided by FirstRanker.com ---
by the action of Fol owing Enzymes:? Isomerase (Enoyl CoA Isomerase)
(For even numbered double bonds MUFAs)
--- Content provided by FirstRanker.com ---
?Reductase (2,4 Dienoyl CoA Reductase)
(For Odd numbered double bonds PUFAS)
--- Content provided by FirstRanker.com ---
?Epimerase(Converts D Isomer to L Isomer)
? Enoyl CoA Isomerase handles
--- Content provided by FirstRanker.com ---
odd numbered double bonds
in MUFAs.
--- Content provided by FirstRanker.com ---
? 2,4 Dienoyl CoA Reductasehandles even numbered
double bonds in PUFAs.
--- Content provided by FirstRanker.com ---
? Usually natural unsaturated fattyacids have cis double bonds.
? Which is transformed to trans
--- Content provided by FirstRanker.com ---
double bonds by the action of an
Isomerase .
--- Content provided by FirstRanker.com ---
? As the next enzyme to act isEnoyl Hydratase ,which acts
only on trans double bonds.
--- Content provided by FirstRanker.com ---
? Enoyl-CoA Isomerase converts
Cis unsaturated Fatty acids to
--- Content provided by FirstRanker.com ---
Trans- 2 Enoyl-CoA? Now the -oxidation can
continue on with the hydration
--- Content provided by FirstRanker.com ---
of the trans- 2-Enoyl-CoA by
Enoyl CoA Hydratase
--- Content provided by FirstRanker.com ---
Oxidation Of
Monounsaturated Fatty Acids
--- Content provided by FirstRanker.com ---
? Oleic acid, Palmitoleic acid? Normal -oxidation for three cycles
? Cis-3 Acyl-CoA cannot be utilized by
Acyl-CoA dehydrogenase
--- Content provided by FirstRanker.com ---
? Enoyl-CoA Isomerase converts this to
trans- 2 Acyl CoA
--- Content provided by FirstRanker.com ---
? -oxidation continues from this pointOxidation Of
--- Content provided by FirstRanker.com ---
Polyunsaturated Fatty AcidsSlightly more complicated
? Same as for Oleic acid, but only up to a point:
--- Content provided by FirstRanker.com ---
? 3 cycles of -oxidation
? Enoyl-CoA Isomerase
--- Content provided by FirstRanker.com ---
? 1 more round of -oxidation? trans- 2, cis- 4 structure is a problem.
? 2,4-Dienoyl-CoA Reductase transform it to odd numbered.
--- Content provided by FirstRanker.com ---
Oxidation of Unsaturated Fatty Acids (Remember they are cis!)
--- Content provided by FirstRanker.com ---
b-oxidation of fatty acids with even
numbered double bonds
? The Oxidation of PUFAs provide less
--- Content provided by FirstRanker.com ---
energy than saturated Fatty acids as
they are less reduced compounds.
--- Content provided by FirstRanker.com ---
? At double bonds the Isomerase actand convert it into Trans ?Enoyl
CoA.
--- Content provided by FirstRanker.com ---
? This bypasses the Acyl-CoA
Dehydrogenase ?FAD linked beta
--- Content provided by FirstRanker.com ---
oxidation reaction.? 1.5 ATP less per double bond.
Ketone Body
--- Content provided by FirstRanker.com ---
Metabolism
Formation And Fates
Of
--- Content provided by FirstRanker.com ---
Ketone Bodies
In Human Body
--- Content provided by FirstRanker.com ---
Ketogenesis And KetolysisOR
Formation And Breakdown
--- Content provided by FirstRanker.com ---
Of Ketone Bodies
What are Ketone Bodies ?
When ? Where? Why?
--- Content provided by FirstRanker.com ---
and How?
Ketone Bodies are Formed
--- Content provided by FirstRanker.com ---
In The Human Body?Incomplete Oxidation
Of Fatty Acids And There Products
--- Content provided by FirstRanker.com ---
? Ketone body Metabolism Includes:?Ketogenesis : Formation of Ketone
bodies
--- Content provided by FirstRanker.com ---
?Ketolysis: Breakdown and Utilization
of Ketone bodies
--- Content provided by FirstRanker.com ---
?Ketosis: Imbalance in Ketogenesis andKetolysis.
Ketogenesis
--- Content provided by FirstRanker.com ---
What Is Ketogenesis?? Ketogenesis is biosynthesis
of Ketone bodies
--- Content provided by FirstRanker.com ---
? In emergency conditions at
Mitochondrial matrix of
--- Content provided by FirstRanker.com ---
Hepatocytes.Condition In Which Ketogenesis Occurs
? Ketogenesis efficiently occur in
--- Content provided by FirstRanker.com ---
Emergency conditions
?Fasting/Starvation Phase
?Low Cel ular Glucose Metabolism
--- Content provided by FirstRanker.com ---
Site For KetogenesisOR
Where Does Ketogenesis
--- Content provided by FirstRanker.com ---
Occurs ?
? Ketone bodies are biosynthesized
--- Content provided by FirstRanker.com ---
in the Liver/Hepatocytes at theMitochondrial Matrix
? Formed Ketone bodies come out of
--- Content provided by FirstRanker.com ---
Mitochondria
? Later they are diffused into the
--- Content provided by FirstRanker.com ---
blood and are? Transported to reach extrahepatic
/peripheral tissues
--- Content provided by FirstRanker.com ---
Who Is ThePrecursor For Ketogenesis ?
?Acetyl CoA is the
--- Content provided by FirstRanker.com ---
precursor/starting
material for
--- Content provided by FirstRanker.com ---
Ketogenesis.Source Of Acetyl-CoA For Ketogenesis
? Ketone bodies are formed from
--- Content provided by FirstRanker.com ---
Acetyl CoA ,obtained throughincreased beta oxidation of
Fatty acids.
--- Content provided by FirstRanker.com ---
? Acetyl-CoA accumulated in
Mitochondrial matrix due to
--- Content provided by FirstRanker.com ---
underutilization via TCAcycle.
Biochemical Basis for
--- Content provided by FirstRanker.com ---
KetogenesisOR
What Favors Ketogenesis ?
--- Content provided by FirstRanker.com ---
OR
Why Ketogenesis Occurs In
--- Content provided by FirstRanker.com ---
Emergency Condition ?What Factors
--- Content provided by FirstRanker.com ---
Promotes/Triggers
Ketogenesis ?
Biochemical Causes for Ketogenesis
--- Content provided by FirstRanker.com ---
? In Emergency Condition
?Due to Cel ular Glucose
--- Content provided by FirstRanker.com ---
deprivation and its metabolism?Low Cel ular Oxaloacetate
?Low Operation of TCA cycle
--- Content provided by FirstRanker.com ---
? Normal Insulin activity do
not promote Ketogenesis.
--- Content provided by FirstRanker.com ---
? Low Insulin activitypromotes Ketogenesis.
Remember
--- Content provided by FirstRanker.com ---
? Availability of Glucose in cel s, donot promote Ketogenesis and
form Ketone bodies.
--- Content provided by FirstRanker.com ---
? Unavailabity of Glucose in cel s
promote Ketogenesis and form
--- Content provided by FirstRanker.com ---
Ketone bodiesWay For KETOGENESIS
REVIEW!
--- Content provided by FirstRanker.com ---
?When the body cel s hasplenty of Carbohydrates
(Glucose) available as
--- Content provided by FirstRanker.com ---
primary energy source,
?Glucose is completely
--- Content provided by FirstRanker.com ---
oxidized to CO2,H2O andATPs.
?When the body has excess
--- Content provided by FirstRanker.com ---
Glucose available it is utilizedas below:
? Required amount of Glucose
--- Content provided by FirstRanker.com ---
is ful y oxidized
?Stored as Glycogen
?Transformed to fatty acids
--- Content provided by FirstRanker.com ---
and stored as TAG.
? When cell Glucose go below sub normal
--- Content provided by FirstRanker.com ---
? Fatty acids undergo -oxidation to formAcetyl-CoA.
? Normally, Acetyl-CoA is further oxidized via
--- Content provided by FirstRanker.com ---
TCA cycle.
In Emergency
--- Content provided by FirstRanker.com ---
How Acetyl-CoA Gets Accumulated
And Diverted For Ketogenesis ?
? In Emergency Condition
--- Content provided by FirstRanker.com ---
? When Cel ular Glucose is low? In response to hormones Glucagon and
Epinephrine
--- Content provided by FirstRanker.com ---
? There is increased Lipolysis and beta
oxidation Fatty acids.
--- Content provided by FirstRanker.com ---
? In emergency conditions? Cellular Glucose levels decreases
? This decreases cel ular Oxalo acetate
(OAA).
--- Content provided by FirstRanker.com ---
?Since source of OAA is Glucose
(By Pyruvate Carboxylation Rxn).
?Also in emergency conditions OAA is
--- Content provided by FirstRanker.com ---
used for Gluconeogenesis whichlowers cel ular OAA.
? OAA is the starting material required to
--- Content provided by FirstRanker.com ---
initiate and operate TCA .? Due to low levels of cel ular OAA, end
product of Fatty acid oxidation- Acetyl-
--- Content provided by FirstRanker.com ---
CoA is not utilized via TCA cycle.
? The underutilized Acetyl-CoA in the
--- Content provided by FirstRanker.com ---
Mitochondrial matrix of Liver getsaccumulated.
What Are
--- Content provided by FirstRanker.com ---
The Steps Of Ketogenesis?
Precursor For Ketogenesis
--- Content provided by FirstRanker.com ---
? Is Acetyl-CoA
? In Emergency condition
? Acetyl ?CoA obtained from increased beta
--- Content provided by FirstRanker.com ---
oxidation of Fatty acids in cel ular Glucose
deprived conditions
--- Content provided by FirstRanker.com ---
? Which accumulates Acetyl-CoA inMitochondrial matrix due to low/no
utilization of Acetyl-CoA via TCA cycle is
--- Content provided by FirstRanker.com ---
diverted for Ketogenesis.
--- Content provided by FirstRanker.com ---
Decarboxylation
q Acetoacetate produces -Hydroxybutyrate
--- Content provided by FirstRanker.com ---
in a reduction reaction catalyzed by -
Hydroxybutyrate Dehydrogenase in the
--- Content provided by FirstRanker.com ---
presence of NADH+H+Isoprenesand
Steroids
--- Content provided by FirstRanker.com ---
Fatty acid2 Acetyl CoA
oxidation to CO2
--- Content provided by FirstRanker.com ---
Citric
-oxidation
--- Content provided by FirstRanker.com ---
acid(excess
cycle
--- Content provided by FirstRanker.com ---
Thiolase
acetyl CoA)
--- Content provided by FirstRanker.com ---
CoAAcetoacetyl CoA
acetyl CoA
--- Content provided by FirstRanker.com ---
HMG-CoA synthase
CoA
--- Content provided by FirstRanker.com ---
MITOCHONDRIAL MATRIXHydroxymethylglutaryl CoA
HMG-CoA-lyase
--- Content provided by FirstRanker.com ---
acetyl CoA
Acetoacetate
--- Content provided by FirstRanker.com ---
NADH(non-enzymatic)
-Hydroxybutyrate
--- Content provided by FirstRanker.com ---
dehydrogenase
Acetone
--- Content provided by FirstRanker.com ---
NAD+-Hydroxybutyrate
--- Content provided by FirstRanker.com ---
Formation ofketone bodies
HMG, 3-hydroxy-3-methylglutaryl
--- Content provided by FirstRanker.com ---
Both enzymes
must be present in
--- Content provided by FirstRanker.com ---
mitochondria forKetogenesis to take
place.
--- Content provided by FirstRanker.com ---
Pathways of ketogenesis in the liver
? Three molecules of Acetyl-
CoA are involved during
--- Content provided by FirstRanker.com ---
the steps of Ketogenesis.
? Ketone bodies can be simply
--- Content provided by FirstRanker.com ---
referred as? Condensed and modified
forms of Acetyl-CoA
--- Content provided by FirstRanker.com ---
?Ketone Bodies are partial yoxidized products of Fatty
Acids (Half broken products
--- Content provided by FirstRanker.com ---
of Fatty acids)
? Obtained through steps of
--- Content provided by FirstRanker.com ---
Ketogenesis.?The end product of Beta oxidation
of Fatty acid - Acetyl-CoA, if not
--- Content provided by FirstRanker.com ---
completely oxidized and utilized via
TCA cycle
--- Content provided by FirstRanker.com ---
? The complex ,impermeable,accumulated Acetyl-CoA is diverted
for Ketogenesis and transformed to
--- Content provided by FirstRanker.com ---
permeable Ketone bodies brought
out of Mitochondria and cel into
--- Content provided by FirstRanker.com ---
blood circulation.Description Of Reaction Of
Ketogenesis
--- Content provided by FirstRanker.com ---
? Two molecules of Acetyl-CoAformed as an end product of -
oxidation condenses with one
--- Content provided by FirstRanker.com ---
another to form Acetoacetyl ?
CoA
--- Content provided by FirstRanker.com ---
? This reaction is by a reversal ofthe Thiolase reaction by an
enzyme Acetoacetyl-CoA Thiolase.
--- Content provided by FirstRanker.com ---
nAcetoacetyl-CoA, which is thestarting material for
Ketogenesis,
--- Content provided by FirstRanker.com ---
nMay also arises directly from
the terminal four carbons of a
--- Content provided by FirstRanker.com ---
fatty acid during -oxidation.? The further steps of Ketogenesis
involves:
--- Content provided by FirstRanker.com ---
? Synthesis and breakdown of
Hydroxy Methyl Glutaryl-CoA/
--- Content provided by FirstRanker.com ---
3-Hydroxy-3-Methylglutaryl-CoA(HMG CoA) from Acetoacetyl-CoA.
? By two key Enzymes:
? HMG-CoA Synthase
--- Content provided by FirstRanker.com ---
? HMG-CoA Lyase?Subsequently in the
second step a third
--- Content provided by FirstRanker.com ---
molecule of Acetyl CoAis added to Acetoacetyl
CoA.
--- Content provided by FirstRanker.com ---
nCondensation of Acetoacetyl-
CoA with another molecule of
--- Content provided by FirstRanker.com ---
Acetyl-CoA to form 3-Hydroxy-3-Methylglutaryl CoA (HMG
CoA)
--- Content provided by FirstRanker.com ---
nCatalyzed by HMG-CoA
Synthase.
? These two steps are identical
--- Content provided by FirstRanker.com ---
to the first two steps in the
Cholesterol biosynthesis
--- Content provided by FirstRanker.com ---
pathway.? In the third step 3-Hydroxy-3-
Methylglutaryl-CoA Lyase
--- Content provided by FirstRanker.com ---
(HMG-CoA Lyase) split off
HMG-CoA
--- Content provided by FirstRanker.com ---
? To release Acetyl-CoA andAcetoacetate.
v Both Acetoacetate and -Hydroxybutyrate
--- Content provided by FirstRanker.com ---
are permeable through mitochondrialmembrane.
v Can be transported across the mitochondrial
--- Content provided by FirstRanker.com ---
membrane and the plasma membrane of
the Liver cells,
--- Content provided by FirstRanker.com ---
Ketone bodies enter to the blood stream tobe used as a fuel by extrahepatocytes/other
cells of the body.
--- Content provided by FirstRanker.com ---
6. In the blood stream, small
amounts of Acetoacetate are
--- Content provided by FirstRanker.com ---
spontaneously (non-enzymatically) Decarboxylated
to Acetone.
--- Content provided by FirstRanker.com ---
7. Acetone is a secondary
,volatile, Ketone body expired
--- Content provided by FirstRanker.com ---
out by Lungs.Acetone is soluble and volatile
and cannot be detected in the
--- Content provided by FirstRanker.com ---
blood and expired out by Lungs.The odor of Acetone may be
detected in the breath
--- Content provided by FirstRanker.com ---
Also the urine of a person has high
level of ketone bodies in the blood
--- Content provided by FirstRanker.com ---
(Ketonuria)Condition where more Acetone is
produced and expired out gives fruity
--- Content provided by FirstRanker.com ---
odor also termed as Acetone
Breath/Kussmauls Breathing.
--- Content provided by FirstRanker.com ---
Acetone Breath is noted in personswith Prolonged Starvation and
Diabetic Ketoacidosis.
--- Content provided by FirstRanker.com ---
? Hydroxy Butyrate is an acidic
compound.
--- Content provided by FirstRanker.com ---
? High levels of Hydroxy Butyrate in
blood
--- Content provided by FirstRanker.com ---
? May lower blood pH and leads to acondition of Metabolic Acidosis.
? Acidosis due to increased Ketone
--- Content provided by FirstRanker.com ---
bodies is termed as Ketoacidosis.
?Ketone bodies formed by
--- Content provided by FirstRanker.com ---
Liver are mobilized out?Circulated in blood and
--- Content provided by FirstRanker.com ---
they may enter extrahepatic tissues for its use.
What are Ketone Bodies?
--- Content provided by FirstRanker.com ---
Ketone bodies areKetone group containing compounds
Obtained from Acetyl-CoA
--- Content provided by FirstRanker.com ---
By Steps of Ketogenesis
Permeable, Soluble
--- Content provided by FirstRanker.com ---
Intermediate Products, of IncompleteOxidation of Fatty Acids
Produced in Emergency Conditions
--- Content provided by FirstRanker.com ---
At Mitochondrial Matrix Of Hepatocytes
Due to Cel ular Glucose Deprivation
--- Content provided by FirstRanker.com ---
Name Three Ketone Bodies
--- Content provided by FirstRanker.com ---
? The Three Ketone bodies presentin human body are:
?Acetoacetate
--- Content provided by FirstRanker.com ---
?Acetone?b- Hydroxybutyrate
--- Content provided by FirstRanker.com ---
Structures OfKetone Bodies
Acetoacetate
--- Content provided by FirstRanker.com ---
Is the First Ketone bodyTo Be Formed
Hence Termed As
--- Content provided by FirstRanker.com ---
Primary Ketone Body
1)Primary Ketone Body:(First Formed Ketone Body)
--- Content provided by FirstRanker.com ---
CH3-CO-CH2-COOH Acetoacetic Acid(Unstable Product)
2)Secondary Ketone bodies:(Derived From Primary Ketone Body)
--- Content provided by FirstRanker.com ---
CH3-CHOH-CH2-COOH -Hydroxybutyric Acid
CH3-CO-CH3
--- Content provided by FirstRanker.com ---
Acetone(Non-metabolized product)
? True Ketone Bodies:
--- Content provided by FirstRanker.com ---
(Possess Ketone group in their structure)?Acetoacetate (Unstable)
?Acetone ( Volatile)
Significance Of
--- Content provided by FirstRanker.com ---
Ketogenesis
? Ketogenesis becomes of
great significant during
--- Content provided by FirstRanker.com ---
starvation.
? It improves survival phase of
--- Content provided by FirstRanker.com ---
vital organs.? Ketone bodies formed by
Ketogenesis serve as an
--- Content provided by FirstRanker.com ---
alternative source of energy
for extra Hepatocytes.
?Brain adapts utilizing
--- Content provided by FirstRanker.com ---
Ketone bodies in
starvation conditions
--- Content provided by FirstRanker.com ---
where there is pooravailability of Glucose.
? After the diet has been
--- Content provided by FirstRanker.com ---
changed to lower blood
Glucose
--- Content provided by FirstRanker.com ---
? After 3 days the Brain gets25% of its energy from
Ketone bodies
--- Content provided by FirstRanker.com ---
? After about 40 days, this
goes up to 70% energy
--- Content provided by FirstRanker.com ---
source to Brain.?Thus Ketogenesis provides
energy for vital organs and
--- Content provided by FirstRanker.com ---
?Maintain there minimal
functions during prolonged
--- Content provided by FirstRanker.com ---
starvationAim Of Steps Of Ketogenesis
OR
--- Content provided by FirstRanker.com ---
What Happens During The Steps
Of Ketogenesis?
? Ketogenesis takes place to transform
--- Content provided by FirstRanker.com ---
impermeable Acetyl CoA molecules ( which are
impermeable through mitochondrial
--- Content provided by FirstRanker.com ---
membranes) to permeable Ketone bodies.? This is By:
? Condensation of Acetyl-CoA molecules
--- Content provided by FirstRanker.com ---
? Removal of complex impermeable CoA from
Acetyl-CoA moieties.
--- Content provided by FirstRanker.com ---
? Forming permeable Acetoacetate (Ketone body)? The main aim to operate
Ketogenesis in Mitochondria
--- Content provided by FirstRanker.com ---
of Hepatocytes is:
?To remove the complex
--- Content provided by FirstRanker.com ---
impermeable CoA fromcarbon units of Acetyl?CoA
?Form permeable
--- Content provided by FirstRanker.com ---
Acetoacetate(4C) to mobilize
out of Liver.
? Ketogenesis removes
--- Content provided by FirstRanker.com ---
impermeable and accumulated
Acetyl-CoA out of Liver
--- Content provided by FirstRanker.com ---
Mitochondria .? Thus steps of Ketogenesis
prevent accumulation of Acetyl-
--- Content provided by FirstRanker.com ---
CoA in matrix of mitochondria.
? Ketogenesis retains and recycle
--- Content provided by FirstRanker.com ---
the CoA pool of Mitochondrialmatrix .
--- Content provided by FirstRanker.com ---
? And the carbon units of Acetyl-CoA are removed as
Acetoacetate.
--- Content provided by FirstRanker.com ---
? Formation of permeable Ketonebody Acetoacetate
? Significantly removes the
--- Content provided by FirstRanker.com ---
accumulated carbon units of
Acetyl-CoA
--- Content provided by FirstRanker.com ---
? In the form of Acetoacetate(Ketone body) from Liver
Mitochondrial matrix.
--- Content provided by FirstRanker.com ---
Regulation of Ketogenesis
HMG COA Synthase
is the Regulatory Enzyme
--- Content provided by FirstRanker.com ---
of Ketogenesis
?HMG-CoA Synthase
--- Content provided by FirstRanker.com ---
activity is induced byincreased fatty
acids in the blood.
--- Content provided by FirstRanker.com ---
? CoA-SH levels regulate theKetogenesis to retain CoA
pool in Mitochondrial matrix.
--- Content provided by FirstRanker.com ---
?Reduced CoA-SH levels
stimulates HMG CoA Synthase
--- Content provided by FirstRanker.com ---
?Increased CoA-SH levelsinhibits HMG CoA Synthase
qKetogenesis is regulated at three
--- Content provided by FirstRanker.com ---
crucial steps:
q Control of Free Fatty acid mobilization
--- Content provided by FirstRanker.com ---
from Adipose tissue (Lipolysis)q The activity of Carnitine
--- Content provided by FirstRanker.com ---
Palmitoyltransferase-I in Liver.q Partition of Acetyl-CoA between the
pathway of Ketogenesis and the Citric
--- Content provided by FirstRanker.com ---
acid cycle by OAA levels.
Regulation of Ketogenesis
--- Content provided by FirstRanker.com ---
Factors Responsible
For Increased Ketogenesis
? Normal y Ketogenesis takes place to
--- Content provided by FirstRanker.com ---
smal extent.
? Ketone bodies are created at
--- Content provided by FirstRanker.com ---
moderate levels in our bodies,? Such as during sleep and other times
? When no Carbohydrates/Glucose are
--- Content provided by FirstRanker.com ---
readily available in cells.?The rate of Ketogenesis
and its efficiency directly
--- Content provided by FirstRanker.com ---
depends upon:
?The Insulin activity
--- Content provided by FirstRanker.com ---
?Levels of Cellular Glucose?Levels of cellular OAA
?Increased and
--- Content provided by FirstRanker.com ---
incomplete oxidation ofFatty acids increases
Ketogenesis.
--- Content provided by FirstRanker.com ---
? The condition where there
is more cellular Glucose
--- Content provided by FirstRanker.com ---
deprivation? More is the efficiency of
Ketogenesis.
--- Content provided by FirstRanker.com ---
?Thus conditions whichaccumulates excess of
Acetyl ?CoA in
--- Content provided by FirstRanker.com ---
Mitochondrial matrix.
?Divert this Acetyl-CoA for
--- Content provided by FirstRanker.com ---
Ketogenesis.Which are The Conditions
Which Deprives
--- Content provided by FirstRanker.com ---
Cellular Glucose And OAA
And
--- Content provided by FirstRanker.com ---
Increases TheRate Of Ketogenesis ?
?Prolonged Starvation
?Diabetes Mellitus
--- Content provided by FirstRanker.com ---
Uncontrolled Condition of
DM: Diabetic Ketoacidosis
--- Content provided by FirstRanker.com ---
?Severe Vomiting?Toxemia of Pregnancy
? Deprivation of Cellular Glucose
? High rates of Fatty acid Oxidation
--- Content provided by FirstRanker.com ---
? Low levels of cellular Oxaloacetate? Under utilization of Acetyl CoA in TCA cycle
? Large accumulated amounts of impermeable
Acetyl-CoA in mitochondrial matrix.
--- Content provided by FirstRanker.com ---
? Accumulated Acetyl-CoA diverted for
Ketogenesis and
--- Content provided by FirstRanker.com ---
? Formation of soluble and permeable Ketonebodies which can be easily mobilized out of the
Mitochondrial matrix.
--- Content provided by FirstRanker.com ---
Inter RelationshipOf
Carbohydrates And Lipid
--- Content provided by FirstRanker.com ---
Metabolism
?Thus low/non availability of
--- Content provided by FirstRanker.com ---
Oxaloacetate in cells in emergencycondition
?Does not oxidize Fatty acid Acetyl-
--- Content provided by FirstRanker.com ---
CoA completely via TCA cycle.
?This results in accumulation of Acetyl
--- Content provided by FirstRanker.com ---
-CoA in Mitochondrial matrix?Which then activates and diverts
Acetyl-CoA for Ketogenesis.
--- Content provided by FirstRanker.com ---
Fats BurnsIn The Flame Of Carbohydrates
MEANS
--- Content provided by FirstRanker.com ---
For Complete Oxidation
Of Fatty Acids
--- Content provided by FirstRanker.com ---
There Needs Presence ofSufficient Glucose In The Cells
? Fat burns under the flame of
--- Content provided by FirstRanker.com ---
Carbohydrates.
? Complete oxidation of Acetyl-CoA
--- Content provided by FirstRanker.com ---
obtained through Fatty acidoxidation
? Requires sufficient Oxaloacetate
--- Content provided by FirstRanker.com ---
which is a source from normal
Glucose metabolism.
? Sufficient cellular Glucose (Flame)
--- Content provided by FirstRanker.com ---
keeps the availability of OAA
? To initiate and operate TCA cycle
--- Content provided by FirstRanker.com ---
and completely oxidize the endproduct of beta oxidation of Fatty
acid Acetyl CoA to CO2 ,H2O and
--- Content provided by FirstRanker.com ---
ATP.
? The entry of Acetyl CoA into the Citric
--- Content provided by FirstRanker.com ---
acid cycle depends on the availabilityof Oxaloacetate.
? The concentration of Oxaloacetate is
--- Content provided by FirstRanker.com ---
lowered
? If Glucose is unavailable (Starvation) or
--- Content provided by FirstRanker.com ---
improperly utilized (Diabetes mellitus).? Oxaloacetate is normally formed from
pyruvate by Pyruvate Carboxylase (
--- Content provided by FirstRanker.com ---
Anaplerotic reaction).
? In Starvation or Diabetes mellitus
the Gluconeogenesis is activated
--- Content provided by FirstRanker.com ---
and Oxaloacetate is consumed in
this pathway.
--- Content provided by FirstRanker.com ---
? Fatty acids are oxidizedproducing excess of Acetyl CoA
which is converted to Ketone
--- Content provided by FirstRanker.com ---
bodies:
?In deprivation of
--- Content provided by FirstRanker.com ---
Glucose?Acetyl CoA is under
utilized and incomplete
--- Content provided by FirstRanker.com ---
oxidized via TCA cycle.
Why Ketogenesis Occur?
--- Content provided by FirstRanker.com ---
The Main aim for the steps ofKetogenesis to occur is:
? To remove the complex, impermeable
--- Content provided by FirstRanker.com ---
,accumulated Acetyl CoA in
Mitochondrial Matrix
--- Content provided by FirstRanker.com ---
? By transforming Acetyl-CoA intopermeable Ketone bodies by removing
CoA moiety.
--- Content provided by FirstRanker.com ---
? Maintain the levels of free CoA pool of
Mitochondrial matrix
? During emergency conditions due to
--- Content provided by FirstRanker.com ---
low cellular Glucose.
? There is alternatively increased beta
--- Content provided by FirstRanker.com ---
oxidation of Fatty acids, producingAcetyl-CoA.
? Deprivation of cellular Glucose also
--- Content provided by FirstRanker.com ---
depletes the levels of Oxalo Acetate
which is an initiator of TCA cycle.
--- Content provided by FirstRanker.com ---
? Low levels of cellular OAA underutilizes the Acetyl-CoA via TCA
cycle.
--- Content provided by FirstRanker.com ---
? Acetyl-CoA which is obtained by
Fatty acid oxidation is less
--- Content provided by FirstRanker.com ---
utilized via TCA cycle .? This accumulates impermeable
Acetyl-CoA in the Mitochondrial
--- Content provided by FirstRanker.com ---
matrix.? To remove the accumulated,
impermeable Acetyl-CoA out
--- Content provided by FirstRanker.com ---
from the Mitochondrial matrix,
there occurs Ketogenesis .
--- Content provided by FirstRanker.com ---
Why Fatty AcidsAre Not Completely Oxidized
In Emergency Conditions?
--- Content provided by FirstRanker.com ---
? Fatty acids in emergency conditionsare not completely oxidized to
CO2,H2O and ATP.
--- Content provided by FirstRanker.com ---
? Fatty acids in emergency undergo
Beta oxidation and produce Acetyl-
--- Content provided by FirstRanker.com ---
CoA? But the produced Acetyl CoA is not
further completely oxidized via TCA
--- Content provided by FirstRanker.com ---
cycle.
? The main facts to have
--- Content provided by FirstRanker.com ---
incomplete oxidation of Fattyacids in emergency condition
are :
--- Content provided by FirstRanker.com ---
?Low levels of cel ular Glucose
and Oxaloacetate
What Makes
--- Content provided by FirstRanker.com ---
The Cellular Oxaloacetate
To Get Depleted
--- Content provided by FirstRanker.com ---
In Emergency Conditions?Remember
?In emergency conditions
--- Content provided by FirstRanker.com ---
where the cellular Glucose is
low
--- Content provided by FirstRanker.com ---
?Oxaloacetate levels also getsdepleted
?Reasons for depletion of cel ular
--- Content provided by FirstRanker.com ---
OAA are:?Glucose is the main source of
OAA
--- Content provided by FirstRanker.com ---
?OAA is, obtained by Pyruvate
Carboxylase reaction
--- Content provided by FirstRanker.com ---
?Thus low availability of cellularGlucose brings low production of
OAA from Glucose in cells.
--- Content provided by FirstRanker.com ---
?OAA is an emergency
condition is diverted for
--- Content provided by FirstRanker.com ---
Gluconeogenesis andtransformed to Glucose.
?Which reduces the actual
--- Content provided by FirstRanker.com ---
OAA levels in the cel s.
Remember
?OAA is an initiator of TCA
--- Content provided by FirstRanker.com ---
operation and
?OAA is required for
--- Content provided by FirstRanker.com ---
complete oxidation forAcetyl-CoA.
Fates Of Ketone Bodies
--- Content provided by FirstRanker.com ---
OR
Ketolysis/Breakdown
--- Content provided by FirstRanker.com ---
OfKetone Bodies
OR
--- Content provided by FirstRanker.com ---
Utilization Of Ketone bodies
Fates of Three Ketone bodies
Uses Of Ketone bodies
--- Content provided by FirstRanker.com ---
?Ketone bodies serves as a
special and major source of
--- Content provided by FirstRanker.com ---
fuel/energy?For certain tissues in
prolonged starvation
--- Content provided by FirstRanker.com ---
phase.
? In the starvation condition
where body has low
--- Content provided by FirstRanker.com ---
Glucose.
? Ketone bodies are used to
--- Content provided by FirstRanker.com ---
generate energy by severalextra hepatic tissues
Fate Of Acetoacetate
--- Content provided by FirstRanker.com ---
?Acetoacetate may be oxidized and serve as
a source of energy to extrahepatocytes.
--- Content provided by FirstRanker.com ---
? If not oxidized to form usable energy,it is converted to next two Ketone bodies
?Acetone and BHB
--- Content provided by FirstRanker.com ---
?If it is not utilized Acetoacetate excretedout through urine.
Fate of -Hydroxybutyrate
--- Content provided by FirstRanker.com ---
?It is not technically a Ketoneaccording to IUPAC
nomenclature.
--- Content provided by FirstRanker.com ---
?It may be used up for energy
source or excreted out through
--- Content provided by FirstRanker.com ---
urine if not used.Fate Of Acetone
?Acetone is not used as
--- Content provided by FirstRanker.com ---
an energy source,
?But it is instead exhaled
--- Content provided by FirstRanker.com ---
or excreted as wastethrough expiration.
Acetone Do not Serve
--- Content provided by FirstRanker.com ---
as Energy Source?Acetone being volatile ,
is not catabolized and
--- Content provided by FirstRanker.com ---
oxidized
?To liberate energy in the
--- Content provided by FirstRanker.com ---
extra hepatocytes.Ketolysis
What Is Ketolysis ?
--- Content provided by FirstRanker.com ---
? Ketolysis is breaking andutilization of Ketone bodies as
energy source
--- Content provided by FirstRanker.com ---
? In the Mitochondrial matrix of
Extra Hepatocytes.
--- Content provided by FirstRanker.com ---
n Ketone bodies have less potentialmetabolic energy than the fatty
acids from which they are derived.
--- Content provided by FirstRanker.com ---
n They make up for this deficiency
by serving as "water-soluble lipid
--- Content provided by FirstRanker.com ---
derivatives" that can be morereadily transported in the blood
plasma.
--- Content provided by FirstRanker.com ---
n During Starvation and in thebodies of uncontrolled Diabetes
mellitus, Ketone bodies are
--- Content provided by FirstRanker.com ---
produced in large amounts
n They become substitutes for
--- Content provided by FirstRanker.com ---
Glucose as the principal fuel forBrain cells.
Site Of Ketolysis
--- Content provided by FirstRanker.com ---
?Mitochondrial
Matrix of Extra
--- Content provided by FirstRanker.com ---
Hepatic Tissues.? Thus primary tissues using Ketone
bodies when available are :
--- Content provided by FirstRanker.com ---
?Brain?Muscle
?Kidney
?Intestine
?But NOT in the Liver
--- Content provided by FirstRanker.com ---
? Ketolysis does not takes place in
Liver
--- Content provided by FirstRanker.com ---
? Due to absence of enzymeThiophorase in Liver which is
required for Ketolysis.
--- Content provided by FirstRanker.com ---
n In early phase of starvationHeart and skeletal muscles
primarily use Ketone bodies
--- Content provided by FirstRanker.com ---
for energy
n Thereby preserving the limited
--- Content provided by FirstRanker.com ---
Glucose and supply it for useby the Brain.
? Brain which normal y depends
--- Content provided by FirstRanker.com ---
on Glucose and do not have
capacity to use Fatty acids.
--- Content provided by FirstRanker.com ---
? during starvation conditionBrain adapts using Ketone
bodies as major energy source
--- Content provided by FirstRanker.com ---
for its survival
--- Content provided by FirstRanker.com ---
v Heart Muscle and the Renal cortexuse Acetoacetate in preference to
Glucose in physiological conditions.
--- Content provided by FirstRanker.com ---
v The Brain adapts to the utilization
of Acetoacetate during Starvation.
--- Content provided by FirstRanker.com ---
Steps Of Ketolysis
Remember
--- Content provided by FirstRanker.com ---
? Ketone bodies will be broken
and utilized in only those
--- Content provided by FirstRanker.com ---
organs/tissues/ cells? Which possess at least some
content of Glucose and Oxalo
--- Content provided by FirstRanker.com ---
acetate.
? Ketolysis breaks the Ketone
--- Content provided by FirstRanker.com ---
bodies and releases Acetyl ?
CoA
--- Content provided by FirstRanker.com ---
? The released Acetyl-CoA isthen final y oxidized via TCA
cycle to CO2,H2O and ATPs.
--- Content provided by FirstRanker.com ---
Conversion of Ketone
--- Content provided by FirstRanker.com ---
Bodies to Acetyl-CoA
n Ketone bodies as an energy source, b-
Hydroxybutyrate and Acetoacetate
--- Content provided by FirstRanker.com ---
n Enter mitochondrial matrix of extra
hepatocytes
--- Content provided by FirstRanker.com ---
n Where they are converted to AcetylCoA,
n Which is further completely oxidized
--- Content provided by FirstRanker.com ---
by the TCA/ Citric acid cycle.
n b-Hydroxybutyrate is oxidized to
--- Content provided by FirstRanker.com ---
Acetoacetate in a reversible reactioncatalyzed by an isozyme of b-
Hydroxybutyrate Dehydrogenase of
--- Content provided by FirstRanker.com ---
extrahepatocytes.
n Remember that this reaction enzyme
--- Content provided by FirstRanker.com ---
is distinct from the Liver enzyme b-Hydroxybutyrate Dehydrogenase.
Use Of Succinyl-CoA
--- Content provided by FirstRanker.com ---
For Thiophorase ReactionIn Ketolysis
? An Enzyme Thiophorase of
--- Content provided by FirstRanker.com ---
Ketolysis requires Succinyl-
CoA for its reaction.
--- Content provided by FirstRanker.com ---
? Succinyl-CoA in this step ofKetolysis is a donor of
Coenzyme A (?CoASH).
--- Content provided by FirstRanker.com ---
Enzyme ThiophoraseIs Natural y
Absent In Liver
--- Content provided by FirstRanker.com ---
nKetone bodies are broken
down only in non hepatic
--- Content provided by FirstRanker.com ---
tissuesnBecause enzyme Thiophorase
is natural y present in al
--- Content provided by FirstRanker.com ---
tissues except Liver.
nIn extrahepatic tissues,
Acetoacetate is activated to
--- Content provided by FirstRanker.com ---
Acetoacetyl-CoA by Succinyl-CoA-
by catalytic activity of Acetoacetate
--- Content provided by FirstRanker.com ---
CoAtransferase/Thiophorase/Succinyl CoA Transferase.
nCoA is transferred from Succinyl-
--- Content provided by FirstRanker.com ---
CoA to form Acetoacetyl-CoA.
? Acetoacetate reacts with
--- Content provided by FirstRanker.com ---
Succinyl CoA to formAcetoacetyl CoA in a
reaction catalyzed by
--- Content provided by FirstRanker.com ---
Succinyl-CoA
Transferase/Thiophorase .
--- Content provided by FirstRanker.com ---
?The Acetoacetyl-CoA is
split to Acetyl-CoA by
--- Content provided by FirstRanker.com ---
Thiolase and oxidizedin the Citric acid cycle.
succinyl-CoA
--- Content provided by FirstRanker.com ---
transferase
Conversion of Acetoacetate to Acetyl CoA.
Significance Of Ketolysis
--- Content provided by FirstRanker.com ---
? Ketone Bodies Serve as a
Fuel for Extrahepatic
--- Content provided by FirstRanker.com ---
Tissues on its oxidation inextra hepatocytes in
Starvation condition.
--- Content provided by FirstRanker.com ---
Calorific value of
Ketone bodies is
--- Content provided by FirstRanker.com ---
7 Cal/gramCalculation
Of
--- Content provided by FirstRanker.com ---
Energetics FromDegradation of Ketone bodies
in Peripheral tissue
--- Content provided by FirstRanker.com ---
1.Acetoacetate is oxidized into 2
Acety1 CoA, which enter the Citric
--- Content provided by FirstRanker.com ---
acid cycle.?Activation of Acetoacetate
consumes 1 ATP , and the total
--- Content provided by FirstRanker.com ---
amount of ATP from metabolism of
2 Acety1 CoA via TCA cycle is 20 ? 1
--- Content provided by FirstRanker.com ---
= 19 ATP2. Conversion of - Hydroxybutyrate
back into Acetoacetate generates 1
--- Content provided by FirstRanker.com ---
NADH ,which produces an additional 2.5ATP
total ATP produce = 22ATP)
--- Content provided by FirstRanker.com ---
(19 +2.5) = 21.5 ATP
After entering the electron transport
--- Content provided by FirstRanker.com ---
chain .Balance and Imbalance
In
--- Content provided by FirstRanker.com ---
Ketone Body Metabolism
? In normal physiological
conditions.
--- Content provided by FirstRanker.com ---
? There occurs balance in
Ketogenesis and Ketolysis
--- Content provided by FirstRanker.com ---
? When the cel ular Carbohydrates and Lipidsare in proper proportionate.
? Then the formation and utilization of Ketone
--- Content provided by FirstRanker.com ---
bodies in the body is balanced and low.
? There is balance in Ketogenesis and Ketolysis
? A very low levels of blood Ketone bodies are
--- Content provided by FirstRanker.com ---
present in normal physiological healthy
condition.
--- Content provided by FirstRanker.com ---
?Normal blood levels of
Ketone bodies is approx.
--- Content provided by FirstRanker.com ---
less than 1 mg%.Levels Of Ketone Bodies
Increases
--- Content provided by FirstRanker.com ---
As The
Starvation Phase Prolongs
?3 days starvation
--- Content provided by FirstRanker.com ---
[KB]=3mM
?3 weeks starvation
--- Content provided by FirstRanker.com ---
[KB]=7mMRate Of Ketolysis
? Rate of Ketolysis in extra
--- Content provided by FirstRanker.com ---
hepatocytes is dependent upon :
?The cel ular levels of Glucose
--- Content provided by FirstRanker.com ---
and Oxaloacetate in extrahepatictissues .
?Rate of Ketolysis
--- Content provided by FirstRanker.com ---
decreases?In more deprived
conditions of cellular
--- Content provided by FirstRanker.com ---
Glucose and OAA.
Imbalance In
--- Content provided by FirstRanker.com ---
Ketone Body Metabolism? Imbalance in Ketone body
metabolism is
--- Content provided by FirstRanker.com ---
? Increased Ketogenesis anddecreased Ketolysis.
? No/Low Ketolysis in body cells
--- Content provided by FirstRanker.com ---
? Accumulates the Ketonebodies in the body.
? Which leads to Ketonemia and
--- Content provided by FirstRanker.com ---
Ketonuria.
Ketosis
Ketosis
--- Content provided by FirstRanker.com ---
?Ketosis is a col ective term
used to refer Ketonemia
--- Content provided by FirstRanker.com ---
and Ketonuria .?Ketosis is a result of
imbalance in Ketone
--- Content provided by FirstRanker.com ---
body metabolism.?Ketosis is a condition
where there is increased
--- Content provided by FirstRanker.com ---
Ketogenesis and
decreased Ketolysis.
Ketonemia
--- Content provided by FirstRanker.com ---
? Ketonemia is an abnormal
increased levels of
--- Content provided by FirstRanker.com ---
circulating Ketone Bodies inBlood more than 1 mg%.
Ketonuria
--- Content provided by FirstRanker.com ---
?Ketonuria is an
abnormal excretion of
--- Content provided by FirstRanker.com ---
Ketone bodies in Urine.? If the blood levels of Ketone
bodies crosses more than the
--- Content provided by FirstRanker.com ---
renal threshold levels of KB(3mg%) it causes-Ketonuria.
Ketoacidosis
--- Content provided by FirstRanker.com ---
? Ketoacidosis is Acidosis caused due
to increased Ketone bodies.
--- Content provided by FirstRanker.com ---
? Ketoacidosis is a type of MetabolicAcidosis .
? It is caused due to imbalance in
--- Content provided by FirstRanker.com ---
Ketone bodies metabolism.
? During KETOACIDOSIS
? Excessive build-up of Ketone
--- Content provided by FirstRanker.com ---
bodies results in Ketosis
eventual y
--- Content provided by FirstRanker.com ---
? Leading to a fal in blood pHdue to the acidic Ketone
bodies.
--- Content provided by FirstRanker.com ---
Ketosis (Ketoacidosis)
Acetone odor in the breath
--- Content provided by FirstRanker.com ---
Acetoacetate and Acetone in urineBiochemical Basis Of Ketosis
?Cel ular Deprivation
--- Content provided by FirstRanker.com ---
Of Glucose?Low Insulin Activity
Conditions Of Ketosis
--- Content provided by FirstRanker.com ---
Conditions Of Ketosis? Prolonged Starvation
? Diabetic Ketoacidosis
(Uncontrol ed Diabetes Mel itus)
--- Content provided by FirstRanker.com ---
? Hyperemesis gravidarum
(Severe Vomiting in first trimester )
--- Content provided by FirstRanker.com ---
? Unbalanced diet i.e. high fat, lowcarbohydrate diet
? Renal Glycosuria
--- Content provided by FirstRanker.com ---
? Alcoholics after binge drinking
and subsequent starvation
Consequences Of Ketosis
--- Content provided by FirstRanker.com ---
?Ketone bodies
accumulation in the
--- Content provided by FirstRanker.com ---
body?May result to negative
long term effects.
--- Content provided by FirstRanker.com ---
?Ketosis create more loadon Lungs and Kidneys
--- Content provided by FirstRanker.com ---
?To expire and excreteout the Ketone Bodies.
? Ketoacidosis lowers blood pH
--- Content provided by FirstRanker.com ---
affects the Enzyme activities
? Deranges the Metabolism
? Affects Normal energy
--- Content provided by FirstRanker.com ---
metabolism
? Affects Water and
--- Content provided by FirstRanker.com ---
Electrolytes Balance? Increased Ketone bodies in
blood is neutralized by the
--- Content provided by FirstRanker.com ---
alkali reserve (blood buffersHCO3-)
? Very excess of Ketone bodies in
--- Content provided by FirstRanker.com ---
blood exhaust HCO3- ,this leads
to Metabolic acidosis.
--- Content provided by FirstRanker.com ---
? If Ketone bodies are far high thanthe capacity of alkali reserve to
neutralize them they will result in
--- Content provided by FirstRanker.com ---
acidemia ?
? Uncompensated acidosis with a
--- Content provided by FirstRanker.com ---
decrease in blood pH (Acid BaseImbalance) which is a serious that
results in death if not treated.
--- Content provided by FirstRanker.com ---
Clinical Features Of KetosisAcid Base Imbalance
? Metabolic Ketoacidosis
--- Content provided by FirstRanker.com ---
? Reduced Alkali reserve(HCO3_)? Kussamaul's Respiration
(Acetone Breath)
Water and Electrolytes
--- Content provided by FirstRanker.com ---
Imbalance? Osmotic Diuresis (Loss of water and
electrolytes along with Ketone bodies)
--- Content provided by FirstRanker.com ---
? Dehydration
? Sodium Loss (Hyponatremia)
? Coma
? Death
--- Content provided by FirstRanker.com ---
Diagnosis Of Ketosis
Detection Of Ketone Bodies
? Volatile Ketone Body ,Acetone is
--- Content provided by FirstRanker.com ---
expired out through Lungs,
? It can be smelled in Ketotic
--- Content provided by FirstRanker.com ---
persons as Acetone breath (WithFruity odor)
? Ketone bodies excreted in Urine
--- Content provided by FirstRanker.com ---
can be detected by carrying
Rothera's Test on Urine specimen.
--- Content provided by FirstRanker.com ---
? Positive Rothera's Test withMagenta color ring in the tube
confirms Ketonuria.
--- Content provided by FirstRanker.com ---
?Ketoacidosis is detectedby analyzing :
?The Blood pH,
--- Content provided by FirstRanker.com ---
Bicarbonates.
? A patient with Diabetic Ketoacidosis
--- Content provided by FirstRanker.com ---
shows:?Urine Benedicts Test- Positive
?Urine Rothera's Test- Positive
--- Content provided by FirstRanker.com ---
? A patient with prolonged Starvation
shows:
--- Content provided by FirstRanker.com ---
?Urine Benedicts Test- Negative?Urine Rothera's Test- Positive
Management Of Ketosis
--- Content provided by FirstRanker.com ---
?Increasing Cellular Glucose?Manages condition of
Ketosis.
? In Starvation Oral or
--- Content provided by FirstRanker.com ---
intravenous Glucose infusion
? In Diabetic Ketoacidosis
--- Content provided by FirstRanker.com ---
infuse Insulin dosage withCheck on Serum Potassium
levels.
--- Content provided by FirstRanker.com ---
Prevention Of Ketosis
? Avoiding cel ular Glucose deprivation
prevents Ketosis.
--- Content provided by FirstRanker.com ---
? A Patient of Diabetes mellitus (Type I) to
prevent Ketosis should control his/her
--- Content provided by FirstRanker.com ---
blood Glucose.? With proper dosage of Insulin and
maintaining cellular Glucose in cells.
--- Content provided by FirstRanker.com ---
Ketogenic Substances
? Substances Promoting Ketogenesis and
--- Content provided by FirstRanker.com ---
increases Ketone bodies are:?Low Cel Glucose
?Excess Fatty acids
?Ketogenic Amino acids
--- Content provided by FirstRanker.com ---
?High Glucagon?Low Insulin
Antiketogenic Substances
? Substances inhibiting Ketogenesis and
--- Content provided by FirstRanker.com ---
decreasing Ketone bodies:
?Sufficient Cel ular Glucose
?Glucogenic Amino acids
--- Content provided by FirstRanker.com ---
?Glycerol?Normal Insulin
Diabetes and
--- Content provided by FirstRanker.com ---
KetoacidosisDiabetic Ketoacidosis
? Diabetic Ketoacidosis is an
--- Content provided by FirstRanker.com ---
Immediate complication of severeuncontrol ed cases of Diabetes
mel itus(Type I/IDDM)
--- Content provided by FirstRanker.com ---
KETOSIS In Diabetes Mellitus
The Absence of Insulin in Diabetes mellitus
--- Content provided by FirstRanker.com ---
? Liver Glucose Metabolism Altered? inhibition of glycolysis
? activation of fatty acid
--- Content provided by FirstRanker.com ---
? activation of gluconeogenesis
mobilization by adipose tissue
--- Content provided by FirstRanker.com ---
? Deficit of oxaloacetate? Large amounts of acetyl CoA which can not be
utilized in Krebs cycle
--- Content provided by FirstRanker.com ---
? Large amounts of ketone bodies (moderately strong acids)
? Severe Acidosis (ketosis)
--- Content provided by FirstRanker.com ---
Impairment of the tissue function, most importantly in the centralnervous system
In Diabetic patients events that can lead to ketosis are:
--- Content provided by FirstRanker.com ---
? Relative or absolute deficiency of insulin? Mobilization of free fatty acids (from adipose Lipolysis)
? Increased delivery of free fatty acids to the liver
--- Content provided by FirstRanker.com ---
? Increased uptake and oxidation of free fatty acids by the liver
? Accelerated production of ketone bodies by the liver
--- Content provided by FirstRanker.com ---
? When there is not enough Insulin in theblood in cases of IDDM
? Cellular Glucose deprivation affects its
--- Content provided by FirstRanker.com ---
efficient use to produce energy.
? Thus, the body utilizes the Lipids for its
--- Content provided by FirstRanker.com ---
energy.? Excessive Lipid degradation with low
Glucose contents , leads to ketones build
--- Content provided by FirstRanker.com ---
up in the blood .
? Ketone bodies then spill over into the
urine so that the body can get rid of
--- Content provided by FirstRanker.com ---
them.
? Acetone can be exhaled through the
--- Content provided by FirstRanker.com ---
lungs. This gives the breath a fruity odor.? Ketones that build up in the body for a
long time lead to serious illness and
--- Content provided by FirstRanker.com ---
coma. (Diabetic Ketoacidosis)
? Ketone bodies Acetoacetate
--- Content provided by FirstRanker.com ---
and Beta Hydroxy Butyrateare acidic
? When produced in excess over
--- Content provided by FirstRanker.com ---
long periods in Diabetes,
causes Diabetic ketoacidosis.
? In a case of severe Diabetic
--- Content provided by FirstRanker.com ---
Ketoacidosis
? The Ketone bodies in the
--- Content provided by FirstRanker.com ---
blood and urine may reachLife threatening
concentrations.
--- Content provided by FirstRanker.com ---
? Blood Ketone bodies may be
up to 100 mg%
--- Content provided by FirstRanker.com ---
(Normal1mg%)? Urinary excretion of Ketone
bodies may be as high as 5 gm
--- Content provided by FirstRanker.com ---
/day.
(Normal 125 mg/day)
Clinical Features OF DKA
--- Content provided by FirstRanker.com ---
Creates Medical Emergency
? Hyperglycemia
? Metabolic Ketoacidosis
--- Content provided by FirstRanker.com ---
? Kussmaul's Respiration? Severe Dehydration /Water
Imbalance
--- Content provided by FirstRanker.com ---
? Electrolyte Imbalance? Acid Base Imbalance
? Coma
? Death
--- Content provided by FirstRanker.com ---
Formation, Utilization, and Excretion of Ketone bodies
Lipogenesis
What Is Lipogenesis?
--- Content provided by FirstRanker.com ---
?Lipogenesis is the
biosynthesis of various
--- Content provided by FirstRanker.com ---
forms of Lipids inhuman body.
When Lipogenesis Occurs?
--- Content provided by FirstRanker.com ---
?Lipogenesis occurs in awell fed condition at
Cytosol of body tissues.
--- Content provided by FirstRanker.com ---
Conditions Favoring Lipogenesis
vExcess of Free Excess Glucose
--- Content provided by FirstRanker.com ---
after heavy Carbohydratemeals.
v Insulin promotes Lipogenesis
--- Content provided by FirstRanker.com ---
Forms Of LipidBiosynthesized In
Human Body Tissues
--- Content provided by FirstRanker.com ---
LIPID BIOSYNTHESIS
? Fatty acid Biosynthesis
? Triacylglycerol Biosynthesis
--- Content provided by FirstRanker.com ---
? Cholesterol Biosynthesis? Phospholipids Biosynthesis
? Glycolipids Biosynthesis
? Eicosanoids Biosynthesis
Where Does Lipogenesis Occur?
--- Content provided by FirstRanker.com ---
Site Of Lipogenesis
?Liver Cytoplasm is the
--- Content provided by FirstRanker.com ---
predominant site forLipogenesis.
?Intestine ,Mammary
--- Content provided by FirstRanker.com ---
glands are other tissuesfor Lipogenesis
? The endogenously
--- Content provided by FirstRanker.com ---
biosynthesized Lipids in Liver are
? Gathered and mobilized out in
--- Content provided by FirstRanker.com ---
the form of Lipoprotein VLDL toextrahepatic tissues.
? VLDL carries endogenous
--- Content provided by FirstRanker.com ---
Lipids from Liver to extraHepatocytes.
? TAG is stored as reserve
--- Content provided by FirstRanker.com ---
food material in Adipose
tissue in unlimited amount.
Precursors For Lipogenesis
--- Content provided by FirstRanker.com ---
Precursors For Lipogenesis
? Acetyl-CoA serve as a precursor
--- Content provided by FirstRanker.com ---
for Fatty acids and Cholesterolbiosynthesis.
? This Acetyl-CoA comes from
--- Content provided by FirstRanker.com ---
excess and free Glucose Oxidation
in a wel fed condition.
?Phospholipid
--- Content provided by FirstRanker.com ---
biosynthesis needs
Lipotropic factors.
--- Content provided by FirstRanker.com ---
Why Lipogenesis Takes Place?Reasons For Lipogenesis
? Free excess Glucose cant be stored in
--- Content provided by FirstRanker.com ---
body cells and tissues as it is .? Free excess Glucose is first converted
and stored in the form of Glycogen
--- Content provided by FirstRanker.com ---
? Storage of Glycogen is limited
? In a well fed condition after limited storage
--- Content provided by FirstRanker.com ---
of Glycogen? When stil there remains Free excess
Glucose
--- Content provided by FirstRanker.com ---
? This free excess Glucose is Oxidized to
Pyruvate via Glycolysis
--- Content provided by FirstRanker.com ---
? Further Pyruvate to Acetyl-CoA via PDHcomplex reaction
? The formed Acetyl-CoA when excess is then
--- Content provided by FirstRanker.com ---
diverted for Lipogenesis.
? Thus Lipogenesis occur in a wel
fed condition
--- Content provided by FirstRanker.com ---
? To transform the free excess
Glucose/Acetyl-CoA in the body
--- Content provided by FirstRanker.com ---
tissues into? Storage able form of Lipid (TAG).
? TAG in the Adiposecytes can be
--- Content provided by FirstRanker.com ---
stored in unlimited amounts.
Hormonal Influence
--- Content provided by FirstRanker.com ---
On Lipogenesis? In a well fed condition
? Hormone Insulin stimulates
--- Content provided by FirstRanker.com ---
Lipogenesis.? Hormone Glucagon inhibits
Lipogenesis.
--- Content provided by FirstRanker.com ---
De Novo Biosynthesis
Of Fatty Acids
?Fatty acid biosynthesis is a
--- Content provided by FirstRanker.com ---
reductive biosynthetic
mechanism.
--- Content provided by FirstRanker.com ---
?To form reduced moleculesof Fatty acid (Palmitate).
? De novo biosynthesis of Fatty
--- Content provided by FirstRanker.com ---
acids is a new biosynthesis of
Fatty acids.
--- Content provided by FirstRanker.com ---
? Using simple carbon unitsAcetyl-CoA and NADPH+H+ to
a long chain fatty acids.
--- Content provided by FirstRanker.com ---
? Palmitic acid (16:0) canbe further modified to
higher Fatty acids .
--- Content provided by FirstRanker.com ---
Site For Fatty Acid Biosynthesis
Organs Involved For
--- Content provided by FirstRanker.com ---
Fatty Acid Synthesis? In humans, Fatty acids are
biosynthesized in Cytosol of:
--- Content provided by FirstRanker.com ---
?Liver (Predominantly)?Adipose tissue
?Intestine
--- Content provided by FirstRanker.com ---
?Lungs
?Brain
--- Content provided by FirstRanker.com ---
?Renal Cortex?Mammary glands during lactation
Reductive Biosynthesis
--- Content provided by FirstRanker.com ---
Of Fatty acids
Extra Mitochondrial/Cytosolic
--- Content provided by FirstRanker.com ---
Biosynthesis of Fatty acids? The biosynthetic pathway of Fatty acids
involves
--- Content provided by FirstRanker.com ---
? The use of reducing equivalentsNADPH+H+ in the reduction steps.
? To form the reduced molecule of fatty
--- Content provided by FirstRanker.com ---
acids,
? Hence it is termed as reductive
--- Content provided by FirstRanker.com ---
Synthesis of Fatty acids.? Fatty acids biosynthesized are
used up for biosynthesis of :
--- Content provided by FirstRanker.com ---
?Triacylglycerol
?Phospholipid
?Glycolipid
?Cholesterol Ester
--- Content provided by FirstRanker.com ---
?Fatty acids are stored asTriacylglycerol, especially
in Adipose tissue.
--- Content provided by FirstRanker.com ---
Biosynthesis Of Palmitic Acid/Palmitate
(C16)
Requirements Of
--- Content provided by FirstRanker.com ---
De novo Biosynthesis
Of Fatty acids
--- Content provided by FirstRanker.com ---
? Precursor for Fatty acidbiosynthesis is Acetyl-CoA
Species comparison of fatty acid synthesis
--- Content provided by FirstRanker.com ---
SpeciesPrincipal Tissue Site
Carbon Source
--- Content provided by FirstRanker.com ---
Poultry
Liver
--- Content provided by FirstRanker.com ---
GlucoseHuman
Liver
--- Content provided by FirstRanker.com ---
Glucose
Pig
--- Content provided by FirstRanker.com ---
AdiposeGlucose
Mouse
--- Content provided by FirstRanker.com ---
Adipose
Glucose
--- Content provided by FirstRanker.com ---
SheepAdipose
Acetate
--- Content provided by FirstRanker.com ---
Cattle
Adipose
--- Content provided by FirstRanker.com ---
Acetate? Requirement of HCO3-
(Bicarbonate Ions) : Provides
--- Content provided by FirstRanker.com ---
CO2 for Acetyl-CoA
Carboxylation Reaction.
? Enzymes Involved:
--- Content provided by FirstRanker.com ---
?Acetyl-CoA Carboxylase
?FAS Multi Enzyme Complex
Coenzyme Required
--- Content provided by FirstRanker.com ---
? Reducing Equivalent :
?NADPH+H+
--- Content provided by FirstRanker.com ---
qThe main source of NADPH+H+ ismainly by the Pentose Phosphate
Pathway.
--- Content provided by FirstRanker.com ---
?The Malic enzyme activity
converts Malate to Pyruvate which
--- Content provided by FirstRanker.com ---
is another source of NADPH+H+
Production of NADPH+ H+
?NADPH+H+ serves as an
--- Content provided by FirstRanker.com ---
electron donor in the
two reactions
--- Content provided by FirstRanker.com ---
?Involving substratereduction in De Novo
Fatty acid biosynthesis.
--- Content provided by FirstRanker.com ---
Who Is The source
Of Acetyl-CoA for Fatty acid
--- Content provided by FirstRanker.com ---
Biosynthesis ??Free and Excess Glucose in
a wel fed condition
--- Content provided by FirstRanker.com ---
?Is the major source of
carbon for the De novo
--- Content provided by FirstRanker.com ---
fatty acid biosynthesis.?Free and excess Glucose
remained after limited
--- Content provided by FirstRanker.com ---
Glycogen storage
?Is used for Acetyl-CoA
--- Content provided by FirstRanker.com ---
production and diverted forthe Fatty acid biosynthesis.
?Glucose is oxidized to
--- Content provided by FirstRanker.com ---
Pyruvate via Glycolysis.?Pyruvate(3C) is then oxidatively
decarboxylated
--- Content provided by FirstRanker.com ---
?To a high energy compound
Acetyl-CoA (2C)in Mitochondria
--- Content provided by FirstRanker.com ---
by PDH Complex.? The excess of Acetyl CoA formed
and present in Mitochondrial
--- Content provided by FirstRanker.com ---
matrix? Is diverted for Denovo
--- Content provided by FirstRanker.com ---
Biosynthesis of Fatty acids.? 8 molecules of Acetyl-CoA (C2)
are required
--- Content provided by FirstRanker.com ---
? For the biosynthesis of
1 molecule of even carbon
--- Content provided by FirstRanker.com ---
Palmitate (C16).?Eight Acetyl-CoA's are
involved.
--- Content provided by FirstRanker.com ---
?To grow a Fatty acidChain of 16-carbons
Fatty Acyl Synthase (FAS)
--- Content provided by FirstRanker.com ---
Multi Enzyme Complex
For De Novo Biosynthesis
--- Content provided by FirstRanker.com ---
Of Fatty AcidsFatty Acyl Synthase (FAS) Complex
? FAS is a Multi Enzyme Complex
--- Content provided by FirstRanker.com ---
Used in De Novo Biosynthesis ofFatty acids.
? Structurally FAS is a Homodimer
--- Content provided by FirstRanker.com ---
? Two alike monomeric subunits
? Linked together in head to tail
--- Content provided by FirstRanker.com ---
fashion (Anti Paral el)Structural Aspects Of FAS
? FAS is Composed of 8
--- Content provided by FirstRanker.com ---
Components? 7 Enzymes and 1 Protein
Three Subunits/Domains
--- Content provided by FirstRanker.com ---
Of FAS Complex
1.Condensation Unit
Has 3 Enzymes
--- Content provided by FirstRanker.com ---
? Acetyl Transacylase
? Malonyl Transacylase
? Beta Keto Acyl Synthase
--- Content provided by FirstRanker.com ---
2. Reduction Unit? ACP- (Acyl Carrier Protein)
? Beta Keto Acyl Reductase
? Dehydratase
--- Content provided by FirstRanker.com ---
? Enoyl Reductase3. Cleavage /Releasing Unit
--- Content provided by FirstRanker.com ---
? Thioesterase (Deacylase)ACP Of FAS Complex
? Acyl Carrier Protein (ACP) of FAS
--- Content provided by FirstRanker.com ---
complex is a carrier of growingAcyl chain
? During De novo biosynthesis of
--- Content provided by FirstRanker.com ---
fatty acids.
The Acyl Carrier Protein
--- Content provided by FirstRanker.com ---
Carrier of Intermediates in Fatty acid synthesis? Discovered by P. Roy Vagelos.
? ACP is a Conjugated
--- Content provided by FirstRanker.com ---
Protein component of FAScomplex.
? ACP is a part of Reduction
--- Content provided by FirstRanker.com ---
unit of FAS complex.
? 4- Phospho Pantethene serve as a
--- Content provided by FirstRanker.com ---
prosthetic group of ACP.? 4-Phospho Pantethene is a
derivative of Vitamin B 5-
--- Content provided by FirstRanker.com ---
Pantothenic acid.
--- Content provided by FirstRanker.com ---
? 4 Phosphopantetheine (Pant)
is covalently linked to Serine
--- Content provided by FirstRanker.com ---
hydroxyl of Protein domain ofACP via a phosphate ester
linkage .
--- Content provided by FirstRanker.com ---
? ACP has ?SH group (Thiol) as
functional group.
--- Content provided by FirstRanker.com ---
? -SH group of ACP is an acceptor ofAcetyl-CoA and Malonyl-CoA
during De novo biosynthesis of a
--- Content provided by FirstRanker.com ---
Fatty acids.
? At the end of Denovo Fatty
acid biosynthesis
--- Content provided by FirstRanker.com ---
? The complete chain of Fatty
acid is linked to ACP of FAS
--- Content provided by FirstRanker.com ---
complex.?The long flexible arm of
Phosphopantetheine
--- Content provided by FirstRanker.com ---
helps its Thiol
?To move from one active
--- Content provided by FirstRanker.com ---
site to another withinthe FAS complex.
--- Content provided by FirstRanker.com ---
Key Player:Acyl Carrier
Protein(ACP)
--- Content provided by FirstRanker.com ---
"Macro"
CoA, carries
--- Content provided by FirstRanker.com ---
growing fattyacid chain
via Thioester
--- Content provided by FirstRanker.com ---
ACP vs. Coenzyme A?Intermediates in synthesis are linked to -SH groups of
Acyl Carrier Proteins (as compared to -SH groups of CoA)
--- Content provided by FirstRanker.com ---
?In terms of
function, ACP is a
--- Content provided by FirstRanker.com ---
large CoA.Acyl Carrier Protein
--- Content provided by FirstRanker.com ---
PhosphopantetheineH
H HO CH3
--- Content provided by FirstRanker.com ---
O
HS-CH
--- Content provided by FirstRanker.com ---
ACP2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser-
Cysteamine
--- Content provided by FirstRanker.com ---
O
O H H
--- Content provided by FirstRanker.com ---
OAcyl carrier protein
10 kDa
--- Content provided by FirstRanker.com ---
H
H HO CH3
--- Content provided by FirstRanker.com ---
OO
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2
--- Content provided by FirstRanker.com ---
O
Adenine
--- Content provided by FirstRanker.com ---
OO H H
O
--- Content provided by FirstRanker.com ---
O
O
--- Content provided by FirstRanker.com ---
HCoenzyme A
O-P-O
--- Content provided by FirstRanker.com ---
OH
OH
--- Content provided by FirstRanker.com ---
FAS Complex Is CodedBy Single Gene
Location Of FAS Complex
--- Content provided by FirstRanker.com ---
?Cytosol?Extra mitochondrial
Hormones Regulating
--- Content provided by FirstRanker.com ---
FAS Complex
? Insulin- Stimulates FAS Complex
--- Content provided by FirstRanker.com ---
? Glucagon-Inhibits FAS ComplexFunctional Parts Of FAS Complex
? FAS complex being dimer has two
--- Content provided by FirstRanker.com ---
functional Units.?-SH (Thiol) group of Cysteine of
condensation Enzyme Keto Acyl
--- Content provided by FirstRanker.com ---
Synthase.
?-SH (Thiol) group of 4 Phospho
--- Content provided by FirstRanker.com ---
Pantethene of ACP.Thiol Cysteine residue
--- Content provided by FirstRanker.com ---
Thiol of Phosphopantetheine? As there are two functional units
? When FAS complex operates at a
--- Content provided by FirstRanker.com ---
time
? There is biosynthesis of two Fatty
--- Content provided by FirstRanker.com ---
acids (Palmitate) molecule.? Rate of Fatty acid
biosynthesis is high in the
--- Content provided by FirstRanker.com ---
well-fed state.X-Ray crystal ographic analysis at 3.2 ? resolution
shows the Dimeric Fatty Acid Synthase to have an
--- Content provided by FirstRanker.com ---
X-shape.
Fatty Acid Synthase Complex
--- Content provided by FirstRanker.com ---
Fatty Acid Synthase Complex
Stages And Steps
--- Content provided by FirstRanker.com ---
Of De Novo Biosynthesis
Of Fatty Acids
Three Stages
--- Content provided by FirstRanker.com ---
Of
De novo Biosynthesis
--- Content provided by FirstRanker.com ---
Of Fatty acidI. Translocation of Acetyl-CoA from
Mitochondria to Cytosol.
--- Content provided by FirstRanker.com ---
I . Carboxylation of Acetyl-CoA to
Malonyl-CoA
--- Content provided by FirstRanker.com ---
I I. Reactions of FAS ComplexStage I
Translocation of Acetyl-CoA
--- Content provided by FirstRanker.com ---
fromMitochondria to Cytosol
Transport Of
--- Content provided by FirstRanker.com ---
Mitochondrial Acetyl-CoA
To Cytosol
Since
--- Content provided by FirstRanker.com ---
Fatty Acid Synthesis
Occurs in the Cytosol
--- Content provided by FirstRanker.com ---
Mitochondria Acetyl-CoAIs to be translocated In Cytosol
Translocation Of Acetyl-CoA
--- Content provided by FirstRanker.com ---
Through
Citrate Shuttle
--- Content provided by FirstRanker.com ---
Citrate Malate PyruvateTransport System
--- Content provided by FirstRanker.com ---
Citrate transportsystem
--- Content provided by FirstRanker.com ---
? The Mitochondrial Acetyl CoAis impermeable due to the
complex CoA .
--- Content provided by FirstRanker.com ---
? Impermeable Acetyl CoA is
transformed to permeable
--- Content provided by FirstRanker.com ---
Citrate by Citrate Synthase.? Citrate is translocated out
in the cytosol.
--- Content provided by FirstRanker.com ---
? Citrate in cytosol is cleavedby Citrate Lyase to liberate
Acetyl-CoA in cytosol.
--- Content provided by FirstRanker.com ---
?Thus Citrate-Malate-Pyruvate
shuttle provides:
--- Content provided by FirstRanker.com ---
?Cytosolic Acetyl CoA?Reducing equivalents
NADPH+H+
--- Content provided by FirstRanker.com ---
?For De novo Fatty acid
biosynthesis
?Acetyl CoA from catabolism of
--- Content provided by FirstRanker.com ---
Carbohydrates and Amino acids is
exported from Mitochondria via the
--- Content provided by FirstRanker.com ---
Citrate transport system?2 ATPs are required during work of
this system.
--- Content provided by FirstRanker.com ---
?Impermeable Acetyl-CoA is
translocated out
--- Content provided by FirstRanker.com ---
?From Mitochondrial Matrix
into Cytosol in the form of
--- Content provided by FirstRanker.com ---
permeable Citrate.?Acetyl-CoA(impermeable)
produced in the Mitochondria is
--- Content provided by FirstRanker.com ---
condensed with Oxaloacetate toform Citrate(permeable) by Citrate
Synthase.
--- Content provided by FirstRanker.com ---
? Permeable Citrate is then
transported out into the Cytosol
--- Content provided by FirstRanker.com ---
? Citrate Lyase in Cytosol act upon
Citrate to regenerate Acetyl-CoA
--- Content provided by FirstRanker.com ---
and Oxaloacetate withconsumption of ATP
?Most Acetyl-CoA used
--- Content provided by FirstRanker.com ---
for FA synthesis comesfrom Mitochondria.
Stage 2
--- Content provided by FirstRanker.com ---
Carboxylation of
Acetyl-CoA to Malonyl-CoA
--- Content provided by FirstRanker.com ---
In CytosolCarboxylation of
Acetyl-CoA(2C)
--- Content provided by FirstRanker.com ---
toMalonyl-CoA(3C)
By
--- Content provided by FirstRanker.com ---
Acetyl CoA Carboxylase (ACC)
Acetyl-CoA Units
--- Content provided by FirstRanker.com ---
Are Activated ToMalonyl-CoA
For Transfer To Growing
--- Content provided by FirstRanker.com ---
Fatty Acid Chain
Malonyl-CoA Is a High Energy
Compound
--- Content provided by FirstRanker.com ---
With a High Energy Bond In Its
Structure
--- Content provided by FirstRanker.com ---
B. Carboxylation of Acetyl CoAEnzyme: Acetyl CoA Carboxylase
Prosthetic group - Biotin
--- Content provided by FirstRanker.com ---
?During biosynthesis of 16 Csaturated Palmitic acid
?There requires total 8
--- Content provided by FirstRanker.com ---
molecules of Acetyl-CoA
? During FAS complex Fatty acid
--- Content provided by FirstRanker.com ---
synthetic steps? Only one molecule of Acetyl-
--- Content provided by FirstRanker.com ---
CoA (C2) enters as it is in thefirst step of Third Stage of
Fatty acid biosynthesis.
--- Content provided by FirstRanker.com ---
? Remaining 7 molecules ofAcetyl-CoA are entered in the
form of Malonyl-CoA (C3).
--- Content provided by FirstRanker.com ---
?Thus Seven Molecules of
Acetyl-CoA are
--- Content provided by FirstRanker.com ---
?Transformed to Sevenmolecules of Malonyl-
CoA.
--- Content provided by FirstRanker.com ---
? Malonyl-CoA is obtained fromcarboxylation reaction of Acetyl-
CoA
--- Content provided by FirstRanker.com ---
? In presence of, enzyme Acetyl
Carboxylase and coenzyme
--- Content provided by FirstRanker.com ---
Biotin and ATP.vConversion of Acetyl-CoA to Malonyl
CoA , is by catalytic activity of Acetyl
--- Content provided by FirstRanker.com ---
CoA Carboxylase , Biotin and ATP.
vThis is an Carboxylation reaction
which provides energy input.
--- Content provided by FirstRanker.com ---
vTo form still more high energycompound Malonyl-CoA(C3).
? This carboxylation reaction
--- Content provided by FirstRanker.com ---
after use of high energy ATP? Builds a high energy bond in
a high energy compound
--- Content provided by FirstRanker.com ---
Malonyl-CoA.
? The input of Acetyl-CoA,
--- Content provided by FirstRanker.com ---
into Fatty acid biosynthesis isby its Carboxylation to
Malonyl-CoA.
--- Content provided by FirstRanker.com ---
vLater this Malonyl CoA cleaves its highenergy bond and looses CO2 and energy
vThis released energy is used for the
--- Content provided by FirstRanker.com ---
condensation reaction during third stage
of Fatty acid biosynthesis for the initation
--- Content provided by FirstRanker.com ---
and growing of Fatty acid.?Thus the spontaneous
Decarboxylation of
--- Content provided by FirstRanker.com ---
Malonyl-CoA?Drives the condensation
reaction of FAS complex.
--- Content provided by FirstRanker.com ---
HCO -
3 + ATP + Acetyl-CoA ADP + Pi + Malonyl-CoA
--- Content provided by FirstRanker.com ---
Acetyl-CoA + HCO -3 + ATP Malonyl-CoA +ADP + Pi
--- Content provided by FirstRanker.com ---
ACC-BiotinAcetyl CoA Carboxylase (ACC)
ACC
--- Content provided by FirstRanker.com ---
Formation of Malonyl-CoA
Acetyl-CoA Carboxylase
--- Content provided by FirstRanker.com ---
has three activities:
?Biotin carrier Protein
?Biotin Carboxylase
--- Content provided by FirstRanker.com ---
?Trans Carboxylase
Bicarbonate is
--- Content provided by FirstRanker.com ---
Phosphorylated, then pickedup by Biotin
Biotin swinging arm
--- Content provided by FirstRanker.com ---
transfers CO2 to acetyl-CoA
Significance Of
--- Content provided by FirstRanker.com ---
Formation of Malonyl-SCoASignificance Of
Formation of Malonyl-SCoA
--- Content provided by FirstRanker.com ---
? This Carboxylation reaction isconsidered as activation step.
? As the breaking of the CO2 bond of
--- Content provided by FirstRanker.com ---
Malonyl-SCoA releases lot of energy
? That "drives" the reaction forward
--- Content provided by FirstRanker.com ---
for condensation reaction of FAScomplex.
? The high energy bond of
--- Content provided by FirstRanker.com ---
Malonyl-CoA is hydrolyzed
later
--- Content provided by FirstRanker.com ---
? To liberate energy which isused up for Condensation
reaction of FAS complex.
--- Content provided by FirstRanker.com ---
?Malonyl-CoA serves asactivated donor of Acetyl
groups in FA synthesis.
--- Content provided by FirstRanker.com ---
? Fatty acid synthesis, from
Acetyl-CoA and Malonyl-
--- Content provided by FirstRanker.com ---
CoA,? Occurs by a series of
reactions catalyzed by FAS
--- Content provided by FirstRanker.com ---
complex.
Stage 3
Reactions Of FAS Complex
--- Content provided by FirstRanker.com ---
During
De Novo Biosynthesis
--- Content provided by FirstRanker.com ---
Of a Fatty Acids /Palmitic Acid? Initation To Form An Acyl Chain
I.
--- Content provided by FirstRanker.com ---
Loading of Precursors ?Acetyl-CoA at SH-ACP
I .
--- Content provided by FirstRanker.com ---
Translocation of Acetyl ?S-ACP to SH-Condensing Enzyme (SH-CE)I I. Entry of Malonyl-CoA and Loading of Malonyl to SH-ACP
IV. Condensation of the Acetyl and Malonyl with decarboxylation
V. Reduction Reaction to transform beta Keto group to Hydroxyl
--- Content provided by FirstRanker.com ---
VI. Dehydration Reaction to transform Hydroxyl group to EnoylVII. Reduction Reaction to transform Enoyl
VII . Translocation of Butyryl From S-ACP to SH-CE
?Elongation and Growing of Acyl Chain
--- Content provided by FirstRanker.com ---
?By Six Time Repetitions of Steps II -VII
?Entry Of 6 Malonyl-CoA's at SH-ACP
?1 Malonyl-CoA in each cycle to ACP-SH
--- Content provided by FirstRanker.com ---
?Cleavage of Fatty acid/ Palmitate?By Thioesterase activity to release Palmitate and FAS
Step I-Step I I
--- Content provided by FirstRanker.com ---
Loading Of PrecursorsAcetyl CoA and Malonyl-CoA
On FAS Complex
--- Content provided by FirstRanker.com ---
By
Acetyl and Malonyl Transacylases
--- Content provided by FirstRanker.com ---
? The Acetyl-CoA (2C) primermolecule is first taken up by ?
SH group of ACP of FAS
--- Content provided by FirstRanker.com ---
complex
? To form Acetyl-S-ACP catalyzed
--- Content provided by FirstRanker.com ---
by Acetyl Transacylase.? Acetyl group from ACP is shifted
--- Content provided by FirstRanker.com ---
to Cysteine-SH of enzyme KetoAcyl Synthase of FAS complex.
--- Content provided by FirstRanker.com ---
? To form Acetyl-S-Enzyme KetoAcyl Synthase in presence of
Acetyl Transacylase.
--- Content provided by FirstRanker.com ---
Loading Of Precursor Acetyl CoA
Step 1:
--- Content provided by FirstRanker.com ---
loading ofAcetyl-CoA
onto Fatty
--- Content provided by FirstRanker.com ---
acid
Synthase
--- Content provided by FirstRanker.com ---
? Malonyl-CoA (3Carbon unit)
enters and is taken up by
--- Content provided by FirstRanker.com ---
-SH of ACP of FAS complex? To form Malonyl-S ACP catalyzed
by Malonyl Transacylase.
--- Content provided by FirstRanker.com ---
Entry Of Malonyl-
CoA
--- Content provided by FirstRanker.com ---
Step 2: loadingof Malonyl-
CoA onto Fatty
--- Content provided by FirstRanker.com ---
acid Synthase
Step IV
--- Content provided by FirstRanker.com ---
Condensation Reaction
Catalyzed By
--- Content provided by FirstRanker.com ---
Beta Keto Acyl SynthaseTo Generate
Keto group
--- Content provided by FirstRanker.com ---
At Beta Carbon Atom
Step 2: Condensation
--- Content provided by FirstRanker.com ---
v Reaction of Malonylgroup with Acetyl
group to form
--- Content provided by FirstRanker.com ---
Acetoacetyl- ACP
v Loss of CO2 and energy
--- Content provided by FirstRanker.com ---
from decarboxylationof Malonyl-CoA.
? The Malonyl Group is
--- Content provided by FirstRanker.com ---
decarboxylated releasingCO2 and high energy
? Which is used for bond
--- Content provided by FirstRanker.com ---
building and condensation
reaction.
--- Content provided by FirstRanker.com ---
? During condensation reactionthere is linking of 2C units of
Acetyl and 2C units of
--- Content provided by FirstRanker.com ---
decarboxylated Malonyl carbon
units
--- Content provided by FirstRanker.com ---
? To form a 4 C Beta Keto ButyrylACP/ Keto Acyl ACP.
--- Content provided by FirstRanker.com ---
Step VReduction Reaction
By
--- Content provided by FirstRanker.com ---
Keto Acyl Reductase
To
--- Content provided by FirstRanker.com ---
Generate Beta Hydroxyl groupStep 3: Reduction of beta Keto
group to form beta Hydroxyl group
--- Content provided by FirstRanker.com ---
Reduction Of Keto Acyl- ACP? Keto Acyl- ACP is reduced to
Hydroxy Acyl- ACP
--- Content provided by FirstRanker.com ---
? In presence of reducing
equivalents NADPH+H+ and
--- Content provided by FirstRanker.com ---
Enzyme Keto Acyl Reductase.Step VI
Dehydration Reaction
--- Content provided by FirstRanker.com ---
By
Dehydratase
--- Content provided by FirstRanker.com ---
ToDevelop Double Bond
--- Content provided by FirstRanker.com ---
Step 4: Dehydration Reaction? Hydroxy Acyl- ACP is
dehydrated to Enoyl CoA/
--- Content provided by FirstRanker.com ---
? Unsaturated Acyl ACP
by the catalytic action of
--- Content provided by FirstRanker.com ---
Dehydratase.Step VI
--- Content provided by FirstRanker.com ---
Reduction ReactionBy
Enoyl-CoA Reductase
--- Content provided by FirstRanker.com ---
To Generate
Saturated Bond
--- Content provided by FirstRanker.com ---
Step 5: Reduction of double bond to Singlebond
--- Content provided by FirstRanker.com ---
? ? Unsaturated Acyl ACP isreduced to Butyryl ?S-ACP
? By NADPH+ H+ and enzyme
--- Content provided by FirstRanker.com ---
Enoyl Reductase.
Overview of
--- Content provided by FirstRanker.com ---
Assembly Stage4 steps:
Condensation
--- Content provided by FirstRanker.com ---
Reduction
Overview of
--- Content provided by FirstRanker.com ---
Assembly Stage
Dehydration
--- Content provided by FirstRanker.com ---
ReductionStep VI I
Translocation Of Butyryl-S CoA to
--- Content provided by FirstRanker.com ---
SH group of Condensing Enzyme
Beta Keto Acyl Synthase
--- Content provided by FirstRanker.com ---
Transfer of Butyryl Chain to SH group
of Beta Keto Acyl Synthase
--- Content provided by FirstRanker.com ---
Elongation and GrowingOf Fatty Acid Chain
--- Content provided by FirstRanker.com ---
To Elongate the Fatty Acid ChainTo 16 Carbon Palmitate
There Should Be Entry
--- Content provided by FirstRanker.com ---
Of
6 More Molecules of
--- Content provided by FirstRanker.com ---
Malonyl CoABy Six Time Repetitions of
Steps I I-VI I
--- Content provided by FirstRanker.com ---
1 Malonyl-CoA entry each
Time
--- Content provided by FirstRanker.com ---
Next cycle begins?Another
Malonyl group is
--- Content provided by FirstRanker.com ---
linked to ACP
Repetitions Of
6 More Cycles
--- Content provided by FirstRanker.com ---
With 5 Steps
? Following transfer of the
--- Content provided by FirstRanker.com ---
growing fatty acid fromPhosphopantetheine to the
Condensing Enzyme's Cysteine
--- Content provided by FirstRanker.com ---
sulfhydryl.
? the cycle begins again, with
--- Content provided by FirstRanker.com ---
another Malonyl-CoA.? Elongation of Fatty Acyl
chain occurs by addition of
--- Content provided by FirstRanker.com ---
Malonyl-CoA after everycycle.
? Every time a new Malonyl ?
--- Content provided by FirstRanker.com ---
CoA enters and taken up by
SH-ACP.
--- Content provided by FirstRanker.com ---
? There are total 7 cycles to utilize? 1 Acetyl-CoA and 7 molecules of
Malonyl-CoA and
--- Content provided by FirstRanker.com ---
? Elongate the Fatty Acid Chain to16 Carbon Palmitate.
Remember
--- Content provided by FirstRanker.com ---
? At Each turn one Molecule of MalonylCoA enters
? Accepted by ACP-SH to form Malonyl ?
--- Content provided by FirstRanker.com ---
SACP.
? Then the repetitions of Condensation
--- Content provided by FirstRanker.com ---
,Reduction , Dehydration andReduction Reactions takes place.
? Decarboxylation of Malonyl-
--- Content provided by FirstRanker.com ---
CoA and
? Reducing power of
--- Content provided by FirstRanker.com ---
NADPH+H+ drive fatty chaingrowth.
? Butyryl group (C4) is shifted to
--- Content provided by FirstRanker.com ---
SH of Cysteine of Keto AcylSynthase.
? SH of ACP is free for accepting
--- Content provided by FirstRanker.com ---
the second molecule of
Malonyl CoA to form Malonyl-S
--- Content provided by FirstRanker.com ---
-ACP.? The steps of Condensation
,Reduction, Dehydration and
--- Content provided by FirstRanker.com ---
Reduction repeats.
? The aim of these steps is to
--- Content provided by FirstRanker.com ---
convert a C=O group to CH2group at carbon of growing
Acyl chain.
--- Content provided by FirstRanker.com ---
?After the completion oftotal 7 cycles
?There is Palmitate
--- Content provided by FirstRanker.com ---
synthesized and is carried
by S-ACP of FAS
--- Content provided by FirstRanker.com ---
complex(Palmitoyl-S-ACP)Cleavage Of Completely
Biosynthesized Palmitate
--- Content provided by FirstRanker.com ---
From ACP of FAS Complex
By Catalytic Activity Of Thioesterase
--- Content provided by FirstRanker.com ---
To ReleaseFree Palmitate and FAS Complex
? The Cleavage enzyme
--- Content provided by FirstRanker.com ---
Thioesterase cleaves theThioester linkage and
? Releases free Palmitic acid
--- Content provided by FirstRanker.com ---
carried by S-ACP of FAS complex.
? Since the FAS complex is a dimeric
--- Content provided by FirstRanker.com ---
unit having two functional units.? During its operation at a time two
--- Content provided by FirstRanker.com ---
molecules of Palmitic acid arebiosynthesized and released.
--- Content provided by FirstRanker.com ---
Fatty Acyl SynthaseThe Steps in the De Novo biosynthesis of fatty acid
Step 1: Loading Reactions
--- Content provided by FirstRanker.com ---
Step 2: Condensation RxnCondensation reaction
--- Content provided by FirstRanker.com ---
Step 3: ReductionReduction Reaction
--- Content provided by FirstRanker.com ---
Step 4: DehydrationDehydration
--- Content provided by FirstRanker.com ---
Step 5: ReductionReduction
--- Content provided by FirstRanker.com ---
Step 6: Next condensationRepetitions Of 7
Cycles
--- Content provided by FirstRanker.com ---
Termination ofFatty Acid
Acyl-CoA
--- Content provided by FirstRanker.com ---
Synthesis
synthetase
--- Content provided by FirstRanker.com ---
Final reaction of FA synthesis is Cleavage
? Palmitoyl-ACP is hydrolyzed by a Thioesterase
--- Content provided by FirstRanker.com ---
Overal Reaction of Palmitate Synthesis from AcetylCoA and Malonyl CoA
Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+
--- Content provided by FirstRanker.com ---
Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O
Summary based on Malonate as an input:
--- Content provided by FirstRanker.com ---
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPHPalmitate + 7 CO2 + 14 NADP+ + 8 CoA
Fatty acid synthesis occurs in the cytosol. Acetyl
--- Content provided by FirstRanker.com ---
-CoA generated in mitochondria is transported
to the cytosol via a shuttle mechanism involving
--- Content provided by FirstRanker.com ---
Citrate.Stoichiometry for Palmitic Acid Synthesis
--- Content provided by FirstRanker.com ---
Diagrammatic View ofFatty Acid Biosynthesis
Energetics Of De Novo Synthesis
--- Content provided by FirstRanker.com ---
Of Fatty Acids?De Novo Fatty acid
biosynthesis is an
--- Content provided by FirstRanker.com ---
Anabolic process
involving use of ATPs.
? Total 23 ATPs are utilized
--- Content provided by FirstRanker.com ---
for the biosynthesis of one
molecule of Palmitate.
--- Content provided by FirstRanker.com ---
?2 ATPs are used for 1 Acetyl-CoA translocationthrough Citrate transport system
? For 8 Acetyl CoA translocation uses 16 ATPs
--- Content provided by FirstRanker.com ---
?1 ATP each is used for Acetyl CoA Carboxylation
to Malonyl CoA.
--- Content provided by FirstRanker.com ---
? To form 7 Malonyl CoAs 7 ATPs are utilized.? 16+7 =23 ATPs Net utilized
Regulation Of Fatty Acid Biosynthesis
--- Content provided by FirstRanker.com ---
The Enzyme Acetyl CarboxylaseIs a
Regulatory ,Key Enzyme
--- Content provided by FirstRanker.com ---
Of
De Novo Fatty acid Synthesis.
? The Committed Step of Fatty Acid Synthesis
--- Content provided by FirstRanker.com ---
? Carboxylation of Acetyl CoA to Malonyl CoA
? By Acetyl CoA Carboxylase - Biotin
?Carboxylation of Acetyl-CoA
--- Content provided by FirstRanker.com ---
to form Malonyl-CoA
?Is an Irreversible, committed
--- Content provided by FirstRanker.com ---
step in Fatty acid biosynthesisModes Of Regulation
Of Acetyl CoA Carboxylase
--- Content provided by FirstRanker.com ---
of FA BiosynthesisAcetyl-CoA Carboxylase is regulated
by 3 modes:
--- Content provided by FirstRanker.com ---
1. Hormonal Influence
2. Al osteric Control
3. Covalent Modification
1. Hormonal Influence
--- Content provided by FirstRanker.com ---
? ACC is an Inducible Enzyme:
?Induced by Insulin
--- Content provided by FirstRanker.com ---
?Insulin activates ACC?Repressed by Glucagon
?Glucagon inhibits ACC
--- Content provided by FirstRanker.com ---
2. Al osteric Modifiers?Citrate Activates Acetyl-CoA
--- Content provided by FirstRanker.com ---
Carboxylase (Feed Forward)
?Fatty Acyl-CoAs inhibit Acetyl-
--- Content provided by FirstRanker.com ---
CoA CarboxylaseAl osteric modification of
Acetyl-Co A Carboxylase
--- Content provided by FirstRanker.com ---
?Activated by: Citrate
?Inhibited by: Long Chain
Fatty Acid
--- Content provided by FirstRanker.com ---
? Body with high levels of cel ularCitrate
? Stimulate De novo biosynthesis of
--- Content provided by FirstRanker.com ---
Fatty acids.
? Body on a high fat diet experience
--- Content provided by FirstRanker.com ---
little if any de novo fatty acidsynthesis.
3. Covalent Modification Of
--- Content provided by FirstRanker.com ---
Acetyl-CoA Carboxylase
? ACC is Activated by :
--- Content provided by FirstRanker.com ---
Dephosphorylation? ACC is Inhibited by:
Phosphorylation
--- Content provided by FirstRanker.com ---
Covalent Modification Of ACC
Covalent Regulation OF
--- Content provided by FirstRanker.com ---
Acetyl CoA Carboxylase
? Activation of ACC
--- Content provided by FirstRanker.com ---
? In a wel Fed state
?Insulin induces Protein Phosphatase
--- Content provided by FirstRanker.com ---
?Activates ACC by De phosphorylation? Inactivation of ACC
--- Content provided by FirstRanker.com ---
? In a Starved state?Glucagon increases cAMP
?Activates Protein kinase A
--- Content provided by FirstRanker.com ---
?Inactivates ACC by Phosphorylation
Acetyl-CoA Carboxylase
--- Content provided by FirstRanker.com ---
Control of Fatty Acid Synthesis
Biosynthesis and Degradation
--- Content provided by FirstRanker.com ---
ofFatty Acid
are
--- Content provided by FirstRanker.com ---
Reciprocal y Regulated
?During Starvation
?Epinephrine & Glucagon Stimulate
--- Content provided by FirstRanker.com ---
Lipolysis
?Brings degradation of FA
--- Content provided by FirstRanker.com ---
?Wel Fed state
v Insulin inhibits Lipolysis
--- Content provided by FirstRanker.com ---
vInsulin Stimulates Fatty acidbiosynthesis.
? ACC also influences degradation of Fatty
--- Content provided by FirstRanker.com ---
acids.
?Malonyl CoA inhibits Carnitine
--- Content provided by FirstRanker.com ---
Acyltransferase I activity.?This limits Beta oxidation of Fatty acids
in Mitochondrial Matrix.
--- Content provided by FirstRanker.com ---
Reciprocal Control
--- Content provided by FirstRanker.com ---
Overview of Fatty Acid Metabolism:Insulin Effects
? Liver
--- Content provided by FirstRanker.com ---
? Increased fatty acid
synthesis
--- Content provided by FirstRanker.com ---
? Glycolysis, PDH, FAsynthesis
? Increased TAG synthesis
--- Content provided by FirstRanker.com ---
and transport as VLDL
? Adipose
--- Content provided by FirstRanker.com ---
? Increased VLDLmetabolism
? lipoprotein lipase
--- Content provided by FirstRanker.com ---
? Increased storage of
lipid
--- Content provided by FirstRanker.com ---
? GlycolysisOverview of Fatty Acid Metabolism:
Glucagon/Epinephrine Effects
--- Content provided by FirstRanker.com ---
? Adipose
? Hormone-sensitive
lipase Increased
--- Content provided by FirstRanker.com ---
? Increased TAG
mobilization
--- Content provided by FirstRanker.com ---
? Increased FAoxidation
? All tissues Except
--- Content provided by FirstRanker.com ---
CNS and RBC
Post-Synthesis Modifications
--- Content provided by FirstRanker.com ---
Of
Biosynthesized Fatty Acids
--- Content provided by FirstRanker.com ---
? C16 Saturated fatty acid (Palmitate) is theproduct which may undergo:
?Elongation
--- Content provided by FirstRanker.com ---
?Unsaturation
?Incorporation to form
--- Content provided by FirstRanker.com ---
Triacylglycerols?Incorporation into Acylglycerol
phosphates to form
--- Content provided by FirstRanker.com ---
Phospholipids
Chain Elongation Of Fatty Acids
Occurs In
--- Content provided by FirstRanker.com ---
Mitochondria
And
--- Content provided by FirstRanker.com ---
Smooth Endoplasmic ReticulumElongation Of Fatty Acids
In Microsomes /Mitochondria
--- Content provided by FirstRanker.com ---
To
Synthesize Long Chain Fatty Acids
? Palmitate biosynthesized by De
--- Content provided by FirstRanker.com ---
Novo Biosynthesis in Cytosol by
the activity of FAS Complex
--- Content provided by FirstRanker.com ---
? Is further elongated to more higherFatty acid either in Mitochondria
/Endoplasmic reticulum.
--- Content provided by FirstRanker.com ---
Mitochondrial Chain Elongation
? Here Acetyl-CoA is successively
--- Content provided by FirstRanker.com ---
added to Fatty acid chain lengthened? In presence of reducing equivalents
NADPH+ H+
--- Content provided by FirstRanker.com ---
? The steps are almost reversal of Beta
Oxidation of Fatty acids.
--- Content provided by FirstRanker.com ---
Microsomal Chain Elongation Of Fatty
Acid
--- Content provided by FirstRanker.com ---
? This is more predominant way ofFatty acid Chain Elongation.
? It involves successive addition of
--- Content provided by FirstRanker.com ---
Malonyl-CoA with the
participation of NADPH+ H+ and
--- Content provided by FirstRanker.com ---
enzyme Elongases.Elongation of Chain (Two Systems)
R-CH2CH2CH2C~SCoA
--- Content provided by FirstRanker.com ---
Malonyl-CoA*
O
--- Content provided by FirstRanker.com ---
(cytosol)HS-CoA
OOC-CH2C~SCoA
--- Content provided by FirstRanker.com ---
CH3C~SCoA
O
--- Content provided by FirstRanker.com ---
COO
2
--- Content provided by FirstRanker.com ---
Acetyl-CoA
R-CH
--- Content provided by FirstRanker.com ---
(mitochondria)2CH2CH2CCH2C~SCoA
O
--- Content provided by FirstRanker.com ---
O
1 NADPH
--- Content provided by FirstRanker.com ---
NADHElongation systems are
2 - H
--- Content provided by FirstRanker.com ---
found in smooth ER and
2O
--- Content provided by FirstRanker.com ---
mitochondria3 NADPH
R-CH2CH2CH2CH2CH2C~SCoA
--- Content provided by FirstRanker.com ---
O
Synthesis Of Unsaturated
Fatty Acids
--- Content provided by FirstRanker.com ---
Mammals can Biosynthesize
Long Chain And Unsaturated
--- Content provided by FirstRanker.com ---
Fatty acidsUsing Elongation And
Desaturation
--- Content provided by FirstRanker.com ---
Desaturation of Fatty Acid Chain InMicrosomes
? Enzyme Fatty Acyl-CoA Desaturase
--- Content provided by FirstRanker.com ---
which is a Flavoprotein
? Helps in creating double bonds and
--- Content provided by FirstRanker.com ---
forming Mono Unsaturated Fattyacids.
? Palmitic acid and Stearic acid
--- Content provided by FirstRanker.com ---
on Desaturation
? Forms corresponding MUFAS
--- Content provided by FirstRanker.com ---
Palmitoleic and Oleic acidrespectively.
? Human body lack the ability to
--- Content provided by FirstRanker.com ---
introduce double bonds beyondcarbon 9 and 10 of Fatty acids.
? Hence body cannot biosynthesize
--- Content provided by FirstRanker.com ---
Linoleic and Linolenic acid and
become dietary essential Fatty acids.
--- Content provided by FirstRanker.com ---
? However Linoleic Acid byChain Elongation and
Desaturation
--- Content provided by FirstRanker.com ---
? Forms Arachidonic acid in
Human body.
--- Content provided by FirstRanker.com ---
Palmitic acid
modifications
--- Content provided by FirstRanker.com ---
Cell makes a pool of
palmitic acid that it can
--- Content provided by FirstRanker.com ---
elongate and/ordesaturate in the ER.
Elongation system is
--- Content provided by FirstRanker.com ---
very similar to synthesis:
2C units added from
--- Content provided by FirstRanker.com ---
malonyl-CoA.Palmitate
Desaturase
--- Content provided by FirstRanker.com ---
16:0 Elongase
Palmitoleate
--- Content provided by FirstRanker.com ---
Stearate16:1(9)
18:0 Desaturase Permitted
--- Content provided by FirstRanker.com ---
Oleate
transitions
--- Content provided by FirstRanker.com ---
18:1(9)in mammals
Essential
--- Content provided by FirstRanker.com ---
fatty acid
Desaturase
--- Content provided by FirstRanker.com ---
LinoleateDesaturase
18:2(9,12)
--- Content provided by FirstRanker.com ---
-Linolenate
-Linolenate
--- Content provided by FirstRanker.com ---
Desaturase18:3(6,9,12)
18:3(9,12,15)
--- Content provided by FirstRanker.com ---
ElongaseEicosatrienoate
Other lipids
--- Content provided by FirstRanker.com ---
Desaturase20:3(8,11,14)Arachidonate
20:4(5,8,11,14)
--- Content provided by FirstRanker.com ---
Differences Between
Beta Oxidation Of Fatty Acid
--- Content provided by FirstRanker.com ---
And
De Novo Biosynthesis Of Fatty Acids
The Biosynthesis and Degradation
--- Content provided by FirstRanker.com ---
Pathways are Different
?The major differences
--- Content provided by FirstRanker.com ---
between Fatty acidbreakdown and
biosynthesis are as:
--- Content provided by FirstRanker.com ---
Beta Oxidation
De Novo Biosynthesis
--- Content provided by FirstRanker.com ---
Palmitic acid Pathway Palmitic acid PathwayCatabolic /Oxidative
Anabolic /Reductive
--- Content provided by FirstRanker.com ---
Occurs In Mitochondria Occurs In CytosolAcetyl CoA is an end
Acetyl CoA is a precursor
--- Content provided by FirstRanker.com ---
productBeta Carbon CH2 is
Beta Carbon C=O is
--- Content provided by FirstRanker.com ---
transformed to C=Oconverted to CH2
Generates 106 ATPs
--- Content provided by FirstRanker.com ---
Utilizes 23 ATPs
Coenzymes FAD and
--- Content provided by FirstRanker.com ---
Coenzymes NADPH +H+ isNAD+ are involved
involved
--- Content provided by FirstRanker.com ---
CoA is an Acyl Carrier ACP is an Acyl Carrier
Fatty Acid Synthesis
Fatty Acid Beta Oxidation
--- Content provided by FirstRanker.com ---
? C=O -CH2
--- Content provided by FirstRanker.com ---
? CH2 C=OTriacylglycerol (TAG) Biosynthesis
Site For TAG Biosynthesis
--- Content provided by FirstRanker.com ---
? TAG biosynthesis predominantlyoccurs in Liver and Adipocytes
TAG Biosynthesis
--- Content provided by FirstRanker.com ---
Takes Place InSmooth Endoplasmic Reticulum
? TAG biosynthesis takes place after De
--- Content provided by FirstRanker.com ---
Novo Biosynthesis of Fatty acids.
? Fatty acids and Glycerol are activated
--- Content provided by FirstRanker.com ---
before TAG biosynthesis.? Fatty acids are activated to Acyl CoA by
Thiokinase
--- Content provided by FirstRanker.com ---
? Glycerol is activated to Glycerol-3-
Phosphate by Glycerol Kinase.
--- Content provided by FirstRanker.com ---
? An Acyl chain is transferred to
Glycerol by Acyl Transferase
--- Content provided by FirstRanker.com ---
producing Lysophosphatidicacid.
? Lysophosphatidic acid is
--- Content provided by FirstRanker.com ---
transformed to Phosphatidic
acid on addition of one more
--- Content provided by FirstRanker.com ---
Acyl chain.? Phosphate group is removed
from Phosphatidic acid to
--- Content provided by FirstRanker.com ---
generate Diacylglycerol.? The addition of third Acyl chain
to Diacylglycerol finally results
--- Content provided by FirstRanker.com ---
in Triacylglycerol.
? Usually a mixed type of TAG is
--- Content provided by FirstRanker.com ---
synthesized in the body.Triacylglycerol Synthesis
Phospholipid Biosynthesis
--- Content provided by FirstRanker.com ---
Glycerophospholipid Synthesis? Glycerophospholipids are
biosynthesized from
--- Content provided by FirstRanker.com ---
Phosphatidic acid and
Diacylglycerol.
--- Content provided by FirstRanker.com ---
? These are also intermediates ofTAG biosynthesis.
--- Content provided by FirstRanker.com ---
Synthesis OF Lecithin and Cephalin? Nitrogenous bases Choline and Ethanolamine
are activated by CTP
--- Content provided by FirstRanker.com ---
? To form CDP-Choline and CDP-Ethanolamine.
? These then added to Phosphatidic acid to
--- Content provided by FirstRanker.com ---
form Lecithin and Cephalin respectively.
? Addition of Serine /Inositol to
--- Content provided by FirstRanker.com ---
Phosphatidic acid forms
Phosphatidyl Serine and
--- Content provided by FirstRanker.com ---
Phosphatidyl InositolDegradation Of Phospholipids
--- Content provided by FirstRanker.com ---
By PhospholipasesOR
Different Types Of Phospholipases
--- Content provided by FirstRanker.com ---
Cholesterol Metabolism? Cholesterol is a C27
compound.
--- Content provided by FirstRanker.com ---
? Cholesterol has a parent
nucleus Cyclo Pentano
--- Content provided by FirstRanker.com ---
Perhydro Phenantherene Ring.Two Forms Of Body Cholesterol
?Free Cholesterol is a
--- Content provided by FirstRanker.com ---
derived Lipid(30%)
?Cholesterol Ester is a
--- Content provided by FirstRanker.com ---
simple Lipid and a bodyWax. (70%)
Cholesterol
--- Content provided by FirstRanker.com ---
? Cholesteryl Ester is astorage and excretory
form of Cholesterol which
is found in most tissues.
--- Content provided by FirstRanker.com ---
Functions Of Cholesterol
Body Cholesterol Is An Essential
? Component of Biomembranes
--- Content provided by FirstRanker.com ---
? Nerve Impulse Conduction? Precursor for:
?Steroidal Hormone biosynthesis
?Bile acid/Bile Salts
--- Content provided by FirstRanker.com ---
?Vitamin D?Remember Cholesterol
is not an energy
--- Content provided by FirstRanker.com ---
producing Lipid.
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
Sources Of Body CholesterolEndogenous And Exogenous
Sources Of Body Cholesterol
--- Content provided by FirstRanker.com ---
? About 1 g/day originates by biosynthesis
? About 0.3 g/day extracted from food
?80% Endogenously produced by
--- Content provided by FirstRanker.com ---
the Liver (0.8 gram/day)
?20% Exogenously comes from the
--- Content provided by FirstRanker.com ---
digestive tract(0.3 gm/day)? Assume 400 mg is an intake of
--- Content provided by FirstRanker.com ---
dietary Cholesterol per day? It absorb about 50% Cholesterol
? 200 mg is absorbed from GIT
? 800 mg of Cholesterol is from de
--- Content provided by FirstRanker.com ---
novo synthesis
Dietary Cholesterol
--- Content provided by FirstRanker.com ---
(Animal Sterol)? Animal products ? eggs
? Animal Brain
? Ghee
--- Content provided by FirstRanker.com ---
? CheeseCholesterol Biosynthesis
Is
--- Content provided by FirstRanker.com ---
Endogenous Source Of BodyCholesterol
Amount Of Cholesterol Biosynthesis
--- Content provided by FirstRanker.com ---
? Endogenously about 1 gm/dayof Cholesterol is biosynthesized.
? Ingestion of excess of
--- Content provided by FirstRanker.com ---
Carbohydrates elevates
Cholesterol biosynthesis.
--- Content provided by FirstRanker.com ---
Conditions Favoring
For
--- Content provided by FirstRanker.com ---
Cholesterol Biosynthesis
? Biosynthesis of Cholesterol takes
place:
--- Content provided by FirstRanker.com ---
?In a wel fed condition
?In excess of free cel ular Glucose
?On stimulation of Insulin
--- Content provided by FirstRanker.com ---
qThe amount of Cholesterolbiosynthesis depends upon
qAvailability of Acetyl-CoA
--- Content provided by FirstRanker.com ---
obtained from Glucose
metabolism in a well fed
--- Content provided by FirstRanker.com ---
state.? Increased free and excess of
cellular Glucose
--- Content provided by FirstRanker.com ---
? Increases the rate of endogenousCholesterol biosynthesis
Cholesterol Synthesis
--- Content provided by FirstRanker.com ---
Simplicity to Complexity
? Al the C27 carbon units of
Cholesterol Structure are
--- Content provided by FirstRanker.com ---
biosynthesized using
? The 2 carbon Acetyl-CoA
--- Content provided by FirstRanker.com ---
units ,obtained fromGlucose metabolism.
Site Of Cholesterol Biosynthesis
--- Content provided by FirstRanker.com ---
Organs and Cel ular Site
For
--- Content provided by FirstRanker.com ---
Cholesterol BiosynthesisOrgans Involved For Cholesterol
Biosynthesis
--- Content provided by FirstRanker.com ---
? Liver (80% )? Intestine (10%)
? Skin (5%)
? Adrenal Cortex
? Ovaries , Testes , Placenta
--- Content provided by FirstRanker.com ---
? Arterial walls (To some extent)? Cholesterol Synthesizing Enzymes
are partly located in:
--- Content provided by FirstRanker.com ---
?Cytoplasm
?Endoplasmic Reticulum
Requirements For Cholesterol
--- Content provided by FirstRanker.com ---
BiosynthesisRequirements For Cholesterol
Biosynthesis
--- Content provided by FirstRanker.com ---
? Metabolic Precursor- Acetyl CoA
(Obtained from excess Glucose
--- Content provided by FirstRanker.com ---
metabolism)? Enzymes ,Coenzymes and Cofactors
? 16 NADPH +H+ (Through HMP Shunt)
? 36 ATPs
--- Content provided by FirstRanker.com ---
Translocation Of Acetyl CoAFrom
Mitochondrial Matrix
--- Content provided by FirstRanker.com ---
To
Cytosol
--- Content provided by FirstRanker.com ---
? Cholesterol is biosynthesizedfrom Cytosolic Acetyl CoA
? Which is transported from
--- Content provided by FirstRanker.com ---
Mitochondria via the Citrate
transport system.
Stages Of Cholesterol Biosynthesis
--- Content provided by FirstRanker.com ---
? Biosynthesis of Cholesterol is a
very complex process
--- Content provided by FirstRanker.com ---
? To understand divided in 5 Stages? Requires more than 25 steps.
? Stage 1.
--- Content provided by FirstRanker.com ---
? Acetyl-CoA forms HMG-CoA and Mevalonate.
? Stage 2.
--- Content provided by FirstRanker.com ---
? Mevalonate forms Active Isoprenoid units(C5)? Stage 3.
? 6 Isoprenoid units form Squalene (C30)
--- Content provided by FirstRanker.com ---
? Stage 4.
? Squalene is converted to Lanosterol
--- Content provided by FirstRanker.com ---
? Stage 5.? Lanosterol is converted to Cholesterol(C27)
Overview/Outline of Cholesterol Synthesis
--- Content provided by FirstRanker.com ---
Initial Activation Steps in Cholesterol Synthesis
Formation of a C10 intermediate GPP
--- Content provided by FirstRanker.com ---
Formation of C15 and C30 intermediates? Michael Palmer 2014
--- Content provided by FirstRanker.com ---
Squalene cyclization yields the first sterolintermediate
Demethylation, desaturation and saturation steps
--- Content provided by FirstRanker.com ---
convert lanosterol to cholesterol
UV-dependent synthesis of Cholecalciferol
Stage I
--- Content provided by FirstRanker.com ---
Synthesis Of HMG CoA
and
--- Content provided by FirstRanker.com ---
MevalonateIt starts by the condensation of
--- Content provided by FirstRanker.com ---
three molecules of AcetylCoA(C2) with the formation of
HMG CoA (C6) by HMG CoA
--- Content provided by FirstRanker.com ---
Synthase (As like In Ketogenesis)
HMG CoA is Reduced to Mevalonic acid (C6)
--- Content provided by FirstRanker.com ---
by reaction requiring NADPH+H+ and enzyme
HMG CoA Reductase.
--- Content provided by FirstRanker.com ---
Two molecules of NADPH are consumed inthe reaction.
Stage 2
--- Content provided by FirstRanker.com ---
Formation Of Isoprenoid Unit
Isopentenyl Pyrophosphate (IPP)
--- Content provided by FirstRanker.com ---
? Mevalonate in three subsequent
steps is
--- Content provided by FirstRanker.com ---
?Phosphorylated with ATPs?Dehydrated and
?Decarboxylated
--- Content provided by FirstRanker.com ---
? To form Isoprenoid unit(C5)-
Isopentenyl pyrophosphate(IPP).
--- Content provided by FirstRanker.com ---
Isomerization Of IPP To DPP
? Isopentenyl Pyrophosphate
--- Content provided by FirstRanker.com ---
(IPP-C5) is isomerized to
Dimethylal yl
--- Content provided by FirstRanker.com ---
Pyrophosphate (DPP-C5)with the Isomerase activity
--- Content provided by FirstRanker.com ---
Stage 3
Synthesis Of Squalene (C30)
--- Content provided by FirstRanker.com ---
Formation OfGeranyl Pyrophosphate
(GPP-C10)
--- Content provided by FirstRanker.com ---
?IPP (C5) and DPP (C5) getcondensed to form
Geranyl Pyrophosphate
--- Content provided by FirstRanker.com ---
(GPP-C10)
Formation OF
--- Content provided by FirstRanker.com ---
Farnesyl Pyrophospate(FPP- C15)
? 1 molecule of GPP condenses with
--- Content provided by FirstRanker.com ---
1 molecule of IPP to form FarnesylPyrophospahte (FPP-C15)
Conversion Of
--- Content provided by FirstRanker.com ---
FPP(C15) to Squalene (C30)
? Two molecules of FPP get
condensed to generate Squalene.
--- Content provided by FirstRanker.com ---
? At smooth Endoplasmic
Reticulum with the catalytic
--- Content provided by FirstRanker.com ---
activity of Squalene SynthaseCoenzyme NADPH+H+ and
Cofactors Mg , Mn and Co
--- Content provided by FirstRanker.com ---
Sage 4
Conversion Of Squalene To Lanosterol
--- Content provided by FirstRanker.com ---
Stage 5
Transformation Of
--- Content provided by FirstRanker.com ---
Lanosterol To Cholesterol
? Lanosterol is converted to
--- Content provided by FirstRanker.com ---
Cholesterol with manysequential steps
--- Content provided by FirstRanker.com ---
? With an intermediatesZymosterol and Desmosterol
--- Content provided by FirstRanker.com ---
Uses Of Body Cholesterol? Cholesterol after its biosynthesis
may serve as precursor for:
--- Content provided by FirstRanker.com ---
?Steroidal Hormones?Bile Acids
?Vitamin D
Fates Of Body Cholesterol
--- Content provided by FirstRanker.com ---
? Cholesterol in human body is component of various
biomembranes of cells.
--- Content provided by FirstRanker.com ---
? Cholesterol helps in nerve impulse conduction? Cholesterol is a precursor for
? Bile acids
? Vitamin D
? Steroidal Hormones-
--- Content provided by FirstRanker.com ---
? Aldosterone
? Estrogen
? Progesterone
? Testosterone
--- Content provided by FirstRanker.com ---
Bile Acids Formed From Cholesterol
? Primary Bile Acids:
--- Content provided by FirstRanker.com ---
? Cholic Acid
? Cheno Deoxy Cholic Acid
--- Content provided by FirstRanker.com ---
? Secondary Bile Acids:? Glycocholic Acid
? Taurocholic Acid
--- Content provided by FirstRanker.com ---
? De- Oxycholic Acid
? Lithocholic Acid
--- Content provided by FirstRanker.com ---
Bile acids are Derived from Cholesterol? Bile acids synthesized from
Cholesterol in the Liver are
--- Content provided by FirstRanker.com ---
carried through bile? Released into the intestine and
reabsorbed in the Jejunum and
--- Content provided by FirstRanker.com ---
Ileum.
Bile Acids are Transformed
--- Content provided by FirstRanker.com ---
ToBile Salts
Role Of Bile Salts
--- Content provided by FirstRanker.com ---
? Bile Salts are effective detergents? They are biosynthesized in the Liver
? Stored & concentrated in the Gallbladder
? Bile salts in Intestine facilitates in
--- Content provided by FirstRanker.com ---
digestion and absorption of intraluminallipids
? Through formation of emulsions and
--- Content provided by FirstRanker.com ---
mixed micel es.
Fate of Bile Salts
Fates of Cholesterol
--- Content provided by FirstRanker.com ---
Diet
De novo synthesis
--- Content provided by FirstRanker.com ---
Cholesterol synthesizedin extrahepatic tissues
Liver cholesterol
--- Content provided by FirstRanker.com ---
pool
Secretion of HDL
--- Content provided by FirstRanker.com ---
Free cholesterolConversion to bile salts/acids
and VLDL
--- Content provided by FirstRanker.com ---
In bile
Regulation Of
--- Content provided by FirstRanker.com ---
Cholesterol BiosynthesisHMG-CoA Reductase
? Is the regulatory/ key enzyme
--- Content provided by FirstRanker.com ---
of Cholesterol Biosynthesis.? The enzyme is stimulated and
inhibited as per the
--- Content provided by FirstRanker.com ---
requirement of bodies need.
?The enzyme HMG-CoA
--- Content provided by FirstRanker.com ---
reductase has half-life of 3 hrs.?Degradation of HMG-CoA
reductase depends on
--- Content provided by FirstRanker.com ---
Cholesterol levels.
Modes Of Cholesterol Regulation
?Hormonal Influence
--- Content provided by FirstRanker.com ---
?Covalent Modification?Feedback Inhibition
Hormonal Regulation
--- Content provided by FirstRanker.com ---
? Insulin In wel fed state:?Stimulates and increases HMG
CoA Reductase
--- Content provided by FirstRanker.com ---
?Increases Cholesterol
Biosynthesis
--- Content provided by FirstRanker.com ---
? Glucagon and Glucocorticoids in
emergency states:
--- Content provided by FirstRanker.com ---
?Inhibits HMG CoA Reductase.?Decreases Cholesterol
Biosynthesis.
Covalent Modification
--- Content provided by FirstRanker.com ---
Of
Regulatory Enzyme
--- Content provided by FirstRanker.com ---
HMG CoA ReductasePhosphorylation
And
--- Content provided by FirstRanker.com ---
Dephosphorylation
Of
--- Content provided by FirstRanker.com ---
HMG CoA Reductase? Short-term regulation of
Cholesterol biosynthesis is by
--- Content provided by FirstRanker.com ---
? Phosphorylation &dephosphorylation of Key
enzyme HMG CoA Reductase
--- Content provided by FirstRanker.com ---
? Phosphorylated ?HMG CoA
Reductase- Inactive Form
--- Content provided by FirstRanker.com ---
? Dephosphorylated-HMG CoAReductase- Active form
HMG CoA Reductase - Phosphorylation
--- Content provided by FirstRanker.com ---
HMG CoA Reductase ? OHHMG CoA Reductase ? P
(active)
--- Content provided by FirstRanker.com ---
(inactive)
AMP-Activated
--- Content provided by FirstRanker.com ---
Protein Kinase (high activity)(+)
phosphatase
--- Content provided by FirstRanker.com ---
AMP
kinase
--- Content provided by FirstRanker.com ---
(+)(+)
AMP-Activated
--- Content provided by FirstRanker.com ---
increase cAMP
insulin
--- Content provided by FirstRanker.com ---
Protein Kinase(low activity)
Glucagon/epi
--- Content provided by FirstRanker.com ---
?Under influence of Hormone Glucagon
?HMG CoA Reductase is Phosphorylated by
cAMP-dependent Protein Kinases.
--- Content provided by FirstRanker.com ---
?Phosphorylation of the Enzyme
inactivates HMG-CoA Reductase
--- Content provided by FirstRanker.com ---
?This inhibits Cholesterol Biosynthesis.?Glucagon, Sterols,
Glucocorticoids & low
--- Content provided by FirstRanker.com ---
ATP levels?Inactivate HMG-CoA
Reductase.
--- Content provided by FirstRanker.com ---
?Under influence of Hormone
Insulin
--- Content provided by FirstRanker.com ---
?HMG CoA Reductase isDephosphorylated
?Which activates HMG-CoA
--- Content provided by FirstRanker.com ---
Reductase.
?This increases Cholesterol
--- Content provided by FirstRanker.com ---
Biosynthesis.? Insulin, Thyroid hormone,
high ATP levels
--- Content provided by FirstRanker.com ---
? Activate the key enzymeHMG-CoA Reductase.
Feed Back Inhibition
--- Content provided by FirstRanker.com ---
? Sufficient amounts of body
Cholesterol regulate its
--- Content provided by FirstRanker.com ---
biosynthesis? By feed back inhibition of
Enzyme HMG CoA Reductase.
--- Content provided by FirstRanker.com ---
? Ingestion of Cholesterol inhibitsendogenous cholesterol synthesis
(control exerted at both transcriptional
--- Content provided by FirstRanker.com ---
and translational levels).
? Gene expression (mRNA production) is
--- Content provided by FirstRanker.com ---
control ed by Cholesterol levelsCholesterol Synthesis
Transcription Control
--- Content provided by FirstRanker.com ---
? Rate of HMG-CoA Reductase
mRNA synthesis is control ed
--- Content provided by FirstRanker.com ---
? By Sterol Regulatory ElementBinding Protein (SREBP)
Competitive Inhibitors Of
--- Content provided by FirstRanker.com ---
Cholesterol Biosynthesis? Drugs like Statins- Lovastatin ,Simvastatin
? Competitive inhibitors of key Enzyme HMG
--- Content provided by FirstRanker.com ---
CoA Reductase of Cholesterol biosynthesis.
? Decreases Endogenous Cholesterol
--- Content provided by FirstRanker.com ---
BiosynthesisLovastatin Inhibits Cholesterol
Biosynthesis
--- Content provided by FirstRanker.com ---
? Lovastatin (Mevinolin) blocks HMG-CoA
Reductase activity and prevents biosynthesis
--- Content provided by FirstRanker.com ---
of Cholesterol.? Lovastatin is an (inactive) Lactone
? In the body, the Lactone is hydrolyzed to
--- Content provided by FirstRanker.com ---
Mevanolinic acid, which is a competitive
inhibitor of HMG CoA reductase.
--- Content provided by FirstRanker.com ---
Drugs Lowering Cholesterol
? Statins ?
--- Content provided by FirstRanker.com ---
decrease HMGCoA Reductase
activity
--- Content provided by FirstRanker.com ---
"Statins" Competitively Inhibit HMG-CoA Reductase
Effects Of "Statins"
(HMG-CoA Reductase Inhibitors)
--- Content provided by FirstRanker.com ---
? Action: Competitively inhibits HMG-CoA reductase, the key enzyme for de
novo cholesterol biosynthesis.
--- Content provided by FirstRanker.com ---
? Effects Of Statins in Human body:? Cells express more LDL receptors
? Decreases serum LDL levels
--- Content provided by FirstRanker.com ---
? Increased HDL levels
? Increased HDL/LDL ratio
--- Content provided by FirstRanker.com ---
? Suppresses production of VLDL in Liver? Advantages: Specific; Effective; Well-tolerated.
? Disadvantages: Hepatotoxicity; myopathy; most expensive; contradicted
--- Content provided by FirstRanker.com ---
in pregnant and nursing women.
Bile salts inhibit the
--- Content provided by FirstRanker.com ---
intestinal HMG CoAReductase.
--- Content provided by FirstRanker.com ---
Drugs Inhibitors of Intestinal Cholesterol uptakeCholesterol Transport
Lipoproteins Involved In Cholesterol
--- Content provided by FirstRanker.com ---
Transport In Blood?Chylomicrons
?LDL
?HDL
--- Content provided by FirstRanker.com ---
? Chylomicrons transport the
dietary Cholesterol
--- Content provided by FirstRanker.com ---
? From intestine to Liver throughlymph and blood
?LDL transports
--- Content provided by FirstRanker.com ---
Endogenous Cholesterol?From Liver to Extrahepatic
tissues.
--- Content provided by FirstRanker.com ---
? HDL transports, Cholesterol
for its excretion
--- Content provided by FirstRanker.com ---
? From Extrahepatic tissues toLiver.
Cholesterol Esterification
--- Content provided by FirstRanker.com ---
? In human body Cholesterol is present intwo forms:
?Free Cholesterol (30%)
--- Content provided by FirstRanker.com ---
?Esterified Cholesterol (70%)? Cholesterol esterification is by enzyme
ACAT and LCAT activity.
--- Content provided by FirstRanker.com ---
? Cholesterol when has to get
excreted out of the body
--- Content provided by FirstRanker.com ---
? It gets esterified to CholesterolEster and transported for its
excretion.
--- Content provided by FirstRanker.com ---
Cholesterol Esterification
LCAT
--- Content provided by FirstRanker.com ---
(Lecithin: Cholesterol Acyltransferase)
Formation of Cholesterol Esters in Lipoproteins
? Acyl-CoA: Cholesterol Acyl
--- Content provided by FirstRanker.com ---
Transferase (ACAT) is an ER
membrane protein
--- Content provided by FirstRanker.com ---
? ACAT transfers fatty acid of CoA toC3 Hydroxyl group of Cholesterol
? Excess Cholesterol is stored as
--- Content provided by FirstRanker.com ---
Cholesterol esters in cytosolic lipid
droplets
--- Content provided by FirstRanker.com ---
? The LCAT activity isassociated to Lipoprotein
HDL.
--- Content provided by FirstRanker.com ---
? HDL is responsible for
transporting of Cholesterol
--- Content provided by FirstRanker.com ---
Ester from extra hepatocytesto Liver for its excretion.
Cholesterol Degradation
--- Content provided by FirstRanker.com ---
and Excretion? About 1 gram of Cholesterol is
catabolized and excreted out
--- Content provided by FirstRanker.com ---
of body via Bile.
? Cholesterol is mostly converted
--- Content provided by FirstRanker.com ---
to Bile acids and Bile salts andexcreted.
?Thus Cholesterol is
--- Content provided by FirstRanker.com ---
excreted in the form ofBile acids and Bile salts.
? Bile acids , Bile Salts and
--- Content provided by FirstRanker.com ---
Cholesterol are carried through
bile to intestine for its excretion.
--- Content provided by FirstRanker.com ---
? Thus half of the body Cholesterolis degraded to Bile acids and
excreted through feces.
--- Content provided by FirstRanker.com ---
? Cholesterol is modified byintestinal bacterial flora to
? Cholestenol and
--- Content provided by FirstRanker.com ---
Coprostenol which are then
excreted out in feces.
--- Content provided by FirstRanker.com ---
? A person is healthy when there isa perfect balance between
?Cholesterol Biosynthesis
--- Content provided by FirstRanker.com ---
?Cholesterol Utilization?Cholesterol Excretion
? This minimizes the chances of
--- Content provided by FirstRanker.com ---
Cholesterol deposition in bloodand tissues.
Note
--- Content provided by FirstRanker.com ---
vIncreased intake of dietaryCholesterol
vDecreases absorption of
--- Content provided by FirstRanker.com ---
Cholesterol
Blood Cholesterol
--- Content provided by FirstRanker.com ---
And ItsClinical Significance
--- Content provided by FirstRanker.com ---
Adult Reference RangesFor Lipid Profile
ANALYTE
--- Content provided by FirstRanker.com ---
REFERENCE RANGE
Total cholesterol
--- Content provided by FirstRanker.com ---
140-200 mg/dLHDL cholesterol
40-75 mg/dL
--- Content provided by FirstRanker.com ---
LDL cholesterol
50-130 mg/dL
--- Content provided by FirstRanker.com ---
Triglyceride60-150 mg/dL
1131
--- Content provided by FirstRanker.com ---
OPTIMAL CHOLESTEROL LEVELS
Blood Cholesterol is associated to
Lipoproteins in 2 forms:
--- Content provided by FirstRanker.com ---
v Free cholesterol (30%)
v Esterified Cholesterol (70%)
--- Content provided by FirstRanker.com ---
Classification of
Plasma Cholesterol Concentrations
--- Content provided by FirstRanker.com ---
Total cholesterolClassification
(mg/dl)
--- Content provided by FirstRanker.com ---
< 200
Desirable
--- Content provided by FirstRanker.com ---
200 - 239Borderline
> 240
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High
HDL Cholesterol
Less than 40 mg/dl
--- Content provided by FirstRanker.com ---
Low level. A major risk factor for CAD
40 to 59 mg/dl
--- Content provided by FirstRanker.com ---
The higher the level the better60 mg/dl and above
High level. Considered protective against CAD
--- Content provided by FirstRanker.com ---
LDL Cholesterol
? Less than 100 mg/dl Optimal
--- Content provided by FirstRanker.com ---
? 100 to 129 mg/dl Near or above optimal? 130 to 159 mg/dl Borderline high
? 160 to 189 mg/dl High
--- Content provided by FirstRanker.com ---
? 190 mg/dl and above Very high/ BAD
Cholesterol
--- Content provided by FirstRanker.com ---
Hypercholesterolemia
Causes, Conditions And
--- Content provided by FirstRanker.com ---
ConsequencesHypercholesterolemia
?Abnormal high levels of
--- Content provided by FirstRanker.com ---
Cholesterol more than thereference range in blood
circulation is termed as
--- Content provided by FirstRanker.com ---
Hypercholesterolemia.
Conditions Of Hypercholesterolemia
--- Content provided by FirstRanker.com ---
? Diabetes mellitus(Increased Intake /Biosynthesis )
? Nephrotic Syndrome
--- Content provided by FirstRanker.com ---
(Defective Lipoprotein metabolism which is not internalized)
? Obstructive Jaundice
--- Content provided by FirstRanker.com ---
(Bile duct obstruction and regurgitation of Bile in Blood)? Hypothyroidism
(Decreased Catabolism and Excretion)
--- Content provided by FirstRanker.com ---
Inherited Hypercholesterolemia? Inherited Hypercholesterolemia is a
genetic cause
--- Content provided by FirstRanker.com ---
? Caused due to defective LDL
receptors on tissues.
--- Content provided by FirstRanker.com ---
? Increases LDL ?Cholesterol in bloodConsequences Of
Hypercholesterolemia
--- Content provided by FirstRanker.com ---
? Increased risk of Atherosclerosis
? Stimulates plaque/thrombus
formation
--- Content provided by FirstRanker.com ---
? May occlude arteries and
? Leads to tissue infarction
? Infarction is irreversible
--- Content provided by FirstRanker.com ---
damage to tissues due toabsence of Oxygen and
Nutrient.
--- Content provided by FirstRanker.com ---
? Infarction of Brain is Stroke
? Infarction of Heart is MI
Hypocholesterolemia
--- Content provided by FirstRanker.com ---
?Abnormal low levels of
Cholesterol in blood
--- Content provided by FirstRanker.com ---
circulation is termed asHypocholesterolemia.
Conditions Of Hypocholesterolemia
--- Content provided by FirstRanker.com ---
?Malnutrition?Malabsorption
?Hyperthyroidism
--- Content provided by FirstRanker.com ---
?Pernicious Anemia
?Hemolytic Anemia
--- Content provided by FirstRanker.com ---
?Liver DisordersConsequences of High Cholesterol
MORTALITY RELATED
--- Content provided by FirstRanker.com ---
DUE TOHIGH CHOLESTEROL
? 1 cause of death: Cardio-vascular diseases
--- Content provided by FirstRanker.com ---
? 3 cause of death: Cerebro-vascular
--- Content provided by FirstRanker.com ---
diseases? 1 + 3 = ~ 40% of al deaths
(Higher risk for Alzheimer & Chronic Liver
--- Content provided by FirstRanker.com ---
disease)
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
FACTORS INFLUENCING CHOLESTEROL LEVELS? Diseases :
?Hypothyroidism
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?Diabetes mellitus
? Lifestyle (Exercise, Stress, Smoking)
? A Family History-Genetic
--- Content provided by FirstRanker.com ---
defects
? Diet- High Fat and Carb diet
?Age
--- Content provided by FirstRanker.com ---
?Weight- Obese?Gender (Men, Menopause)
HDL cholesterol levels lower than
--- Content provided by FirstRanker.com ---
<40 mg/dl)increase a person's risk of
developing coronary artery
--- Content provided by FirstRanker.com ---
disease, especially in people who
also have high total cholesterol
--- Content provided by FirstRanker.com ---
levels.? HDL Cholesterol levels
greater than 100 mg/dl
--- Content provided by FirstRanker.com ---
?Also increase the risk indeveloping coronary artery
disease and Stroke.
--- Content provided by FirstRanker.com ---
CHOLESTEROL PROFILE
IMPROVEMENT STRATEGY
vIMPROVING DIET
--- Content provided by FirstRanker.com ---
vLIFE STYLE MODIFICATIONS
v REGULAR EXERCISE
--- Content provided by FirstRanker.com ---
vSMOKING, ALCOHILISM CESSATION
vSTRESS REDUCTION
--- Content provided by FirstRanker.com ---
v WEIGHT CONTROLv BEHAVIOR CHANGE
--- Content provided by FirstRanker.com ---
? When diet changes fail.
? Hypolipidemic drugs will
--- Content provided by FirstRanker.com ---
reduce serum Cholesterol and
Triacylglycerol.
Therapeutic Principle:
--- Content provided by FirstRanker.com ---
Lowering Blood Cholesterols
Inhibition of Cholesterol
--- Content provided by FirstRanker.com ---
biosynthesisInhibition of Cholesterol
--- Content provided by FirstRanker.com ---
uptake from GITInhibition of Bile acid reuptake
--- Content provided by FirstRanker.com ---
LDL apheresis (Taking away)Inhibition of Cholesterol Ester
Transfer Protein (CETP) to some
--- Content provided by FirstRanker.com ---
extent increases HDL levels.
? Cholestyramine Resins:
Block reabsorption of bile acids.
--- Content provided by FirstRanker.com ---
? Sitosterols:
acts by blocking the absorption of
--- Content provided by FirstRanker.com ---
Cholesterol from thegastrointestinal tract.
? Mevocore or Lovastatin:
--- Content provided by FirstRanker.com ---
inhibitors of HMG-CoA Reductase
Lipoprotein Metabolism
Role Of Lipoproteins
--- Content provided by FirstRanker.com ---
In
Health And Disease
--- Content provided by FirstRanker.com ---
Transportation Of LipidsLipoprotein Metabolism
And
--- Content provided by FirstRanker.com ---
Related DisordersWhat are Lipoproteins ?
vLipid compounds: Relatively
--- Content provided by FirstRanker.com ---
insoluble in watervTherefore, they are transported
in plasma and Lymph (aqueous
--- Content provided by FirstRanker.com ---
phase) as Lipoproteins
?Lipoproteins are complex
--- Content provided by FirstRanker.com ---
macromolecules?Biosynthesized by
aggregation of Lipids and
--- Content provided by FirstRanker.com ---
Proteins.
? Lipoproteins are compound
Lipids/Conjugated Proteins.
--- Content provided by FirstRanker.com ---
? Lipoproteins acquire charge and
made soluble in aqueous phase.
--- Content provided by FirstRanker.com ---
Structure Of Lipoproteins?Non polar Lipids are at
center
--- Content provided by FirstRanker.com ---
?Polar Lipids and
Apoproteins are present
--- Content provided by FirstRanker.com ---
at periphery.Hydrophobic lipids
--- Content provided by FirstRanker.com ---
Amphiphilic lipidsStructure Of Lipoprotein
--- Content provided by FirstRanker.com ---
Structure of lipoprotein
--- Content provided by FirstRanker.com ---
Hydrophobic lipids (TAG, CE) in the coreAmphiphilic lipids (C, PL) and proteins on the
surface
--- Content provided by FirstRanker.com ---
Plasma Lipoproteins (Structure)
? Non-covalent
--- Content provided by FirstRanker.com ---
assemblies of lipidsand proteins
? LP core
--- Content provided by FirstRanker.com ---
? Triglycerides
? Cholesterol esters
? LP surface
--- Content provided by FirstRanker.com ---
? Phospholipids
? Proteins
Function as transport vehicles
--- Content provided by FirstRanker.com ---
? Cholesterol
for triacylglycerols and
--- Content provided by FirstRanker.com ---
cholesterol in the bloodFunction/Role Of Lipoproteins
?Lipoproteins function
--- Content provided by FirstRanker.com ---
as transport vehicles?For transportation of
insoluble form of
--- Content provided by FirstRanker.com ---
Lipids in blood plasma.
? Lipoproteins deliver the
--- Content provided by FirstRanker.com ---
lipid components
(Cholesterol and TAG etc.)
--- Content provided by FirstRanker.com ---
from one tissues tovarious tissues for their
utilization.
--- Content provided by FirstRanker.com ---
? Various Lipoproteins formed within
the body cells
--- Content provided by FirstRanker.com ---
? Serves in transportation ofexogenous (Dietary Source) and
endogenous (Those Lipids
--- Content provided by FirstRanker.com ---
biosynthesized)lipids
? From one organ to another
--- Content provided by FirstRanker.com ---
through aqueous phase of Lymphand blood.
Lipoproteins Role Facilitate
--- Content provided by FirstRanker.com ---
?Substrates for Energy Metabolism (TAG)?Provide Essential components for cells
(PL, C)
--- Content provided by FirstRanker.com ---
?Precursors for Hormones (Cholesterol)?Carries Lipid soluble Vitamins
?Precursors for Bile acids and Bile salts (C)
Types Of Lipoproteins
--- Content provided by FirstRanker.com ---
? There are different types of Lipoproteinsdepending upon:
I. Site of Lipoprotein Biosynthesis
--- Content provided by FirstRanker.com ---
I . Lipid ContentsI I. Apoprotein Contents and Type
IV. Diameter /Size
V. Transport Destination
VI. Ultracentrifugation
--- Content provided by FirstRanker.com ---
VI . Electrophoretic PatternLipoproteins
Site Of
--- Content provided by FirstRanker.com ---
Destination
Major
--- Content provided by FirstRanker.com ---
BiochemicalSynthesis
Lipids
--- Content provided by FirstRanker.com ---
Functions
Chylomicrons Intestine Liver
--- Content provided by FirstRanker.com ---
ExogenousDeliver lipids of
Triacylglycerol
--- Content provided by FirstRanker.com ---
dietary origin to
Liver and
--- Content provided by FirstRanker.com ---
AdiposecytesVLDLs
Liver
--- Content provided by FirstRanker.com ---
Extra Hepatic
Endogenous
--- Content provided by FirstRanker.com ---
DeliverTissues
Triacylglycerol
--- Content provided by FirstRanker.com ---
endogenously
produced Lipids
--- Content provided by FirstRanker.com ---
toExtrahepatocytes
LDLs
--- Content provided by FirstRanker.com ---
Intravascular Extra hepatic
Cholesterol
--- Content provided by FirstRanker.com ---
Deliverremoval of
Tissues
--- Content provided by FirstRanker.com ---
endogenously
Triacylglycerol
--- Content provided by FirstRanker.com ---
producedfrom VLDL
cholesterol to
--- Content provided by FirstRanker.com ---
Extrahepatocytes
HDLs
--- Content provided by FirstRanker.com ---
Liver andLiver and steroid-
Phospholipid
--- Content provided by FirstRanker.com ---
Remove and
intestine
--- Content provided by FirstRanker.com ---
hormone-Cholesterol
degrade
--- Content provided by FirstRanker.com ---
producing glands
Cholesterol.
--- Content provided by FirstRanker.com ---
CM VLDL LDL HDL
Density (g/mL <0.96 0.96-1.006 1.006-1.063 1.063-1.21
Diameter (nm) 100-1000 30-90 20-25 10-20
Apolipoprotein A,C,E,B48 A,C,E,B100 B100 A,C,D,E
--- Content provided by FirstRanker.com ---
Composition (%)Proteins 2 10 20 40
Lipids 98 90 80 60
Lipid composition (%)
TAG 88 55 12 12
--- Content provided by FirstRanker.com ---
CE+C 4 24 59 40PL 8 20 28 47
Free fatty acid - 1 1 1
Chylomicrons
--- Content provided by FirstRanker.com ---
Very low density
Lipoprotein (VLDL)
--- Content provided by FirstRanker.com ---
Low densityLipoprotein (LDL)
High density
--- Content provided by FirstRanker.com ---
Lipoprotein (HDL)
Lipoproteins
--- Content provided by FirstRanker.com ---
Lipoprotein Nomenclature, Compositionand separation
CM
--- Content provided by FirstRanker.com ---
VLDL
LDL
--- Content provided by FirstRanker.com ---
HDLMajor ApoB 48 ApoB 100 ApoB 100 ApoA-I
Protein
--- Content provided by FirstRanker.com ---
Major TAG
TAG CE
--- Content provided by FirstRanker.com ---
PLand CE
Lipid
--- Content provided by FirstRanker.com ---
Ultracentrifugation
of
--- Content provided by FirstRanker.com ---
Lipoproteins
Lipoprotein
--- Content provided by FirstRanker.com ---
Particles with distinct densities1.Electrophoresis
--- Content provided by FirstRanker.com ---
2. Ultra centrifugation methodmethod:
CM (chylomicron )
--- Content provided by FirstRanker.com ---
CM (chylomicron)
Slow
--- Content provided by FirstRanker.com ---
very low density lipoprotein (Slow
VLDL)
--- Content provided by FirstRanker.com ---
-Lipoprotein
low density lipoprotein ( LDL)
--- Content provided by FirstRanker.com ---
pre -Lipoproteinhigh density lipoprotein (HDL)
Fast
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
High- Lipoprotein
Lipoprotein Electrophoresis
--- Content provided by FirstRanker.com ---
Plasma Lipoproteins
For Triacylglycerol Transport (TAG-rich):
--- Content provided by FirstRanker.com ---
- Chylomicrons: TAG of dietary origin
- VLDL:TAG of Endogenous (hepatic)
--- Content provided by FirstRanker.com ---
synthesisFor Cholesterol transport (cholesterol-rich):
LDL: Mainly Free Cholesterol
--- Content provided by FirstRanker.com ---
HDL: Mainly esterified Cholesterol
Important Enzymes and
Proteins
--- Content provided by FirstRanker.com ---
Involved in
Lipoprotein Metabolism
--- Content provided by FirstRanker.com ---
Lipoprotein LipaseOR
A Clearing Factor
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase (LPL)LPL is located in the
?
--- Content provided by FirstRanker.com ---
endothelial lining ofblood vessels.
Lipoprotein Lipase (LPL)
--- Content provided by FirstRanker.com ---
? LPL is an extracel ular enzyme,
anchored by Heparan sulfate to the
--- Content provided by FirstRanker.com ---
capil ary wal s of most tissues? It is predominantly present in
Adipose tissue, Cardiac & Skeletal
--- Content provided by FirstRanker.com ---
muscle
? LPL requires Apo C-II for its activation
? LPL degrades TAG into Glycerol and free
--- Content provided by FirstRanker.com ---
fatty acids by its activity.
? Insulin stimulates its synthesis and
--- Content provided by FirstRanker.com ---
transfer to the luminal surface of thecapil ary.
Lipoprotein Lipases
--- Content provided by FirstRanker.com ---
? Lipoprotein Lipases in capil aries of
adipose and muscle tissues hydrolyze
--- Content provided by FirstRanker.com ---
TAG in VLDLs.? VLDLs become IDLs
? IDLs looses more TAG and become LDLs.
? LDLs are less in TAG and rich in
--- Content provided by FirstRanker.com ---
Cholesterol and Cholesterol-esters.
? Lipoprotein Lipase act upon TAG
of Lipoproteins and hydrolyze it
--- Content provided by FirstRanker.com ---
? LPL Transforms the ?
?Chylomicron to Chylomicron
--- Content provided by FirstRanker.com ---
remnant?VLDL to LDL
? LPL clear the circulating
--- Content provided by FirstRanker.com ---
Lipoproteins from blood
hence it is termed as
--- Content provided by FirstRanker.com ---
Clearing Factor.? Type I Hypolipoproteinemia
? This is termed as Familial
Lipoprotein Lipase deficiency
--- Content provided by FirstRanker.com ---
? Caused due to:
?LPL defect
?Apo C-I is defect
--- Content provided by FirstRanker.com ---
? LPL Hydrolyzes Triacylglycerol (TAG)
in the core of CM and VLDL to free
--- Content provided by FirstRanker.com ---
Fatty acids and Glycerol.? The released free fatty acids and
Glycerol
--- Content provided by FirstRanker.com ---
? Then enter into the tissue, mainly
adipose, heart, and muscle (80%),
--- Content provided by FirstRanker.com ---
while about 20% goes indirectly to theLiver.
--- Content provided by FirstRanker.com ---
LPL Mediated Fatty Acid Uptake
--- Content provided by FirstRanker.com ---
Hepatic Lipase (HL)? HL is bound to the surface of Liver
cells
--- Content provided by FirstRanker.com ---
? Hydrolyzes TAG to free fatty acidsand Glycerol
?HL is concerned with TAG hydrolysis
--- Content provided by FirstRanker.com ---
in Chylomicron remnants and HDLcoming to Liver.
--- Content provided by FirstRanker.com ---
LCAT(Lecithin Cholesterol Acyltransferase)
Formation of Cholesterol Esters in Lipoproteins
--- Content provided by FirstRanker.com ---
? LCAT is associated with HDL
Lipoprotein.
--- Content provided by FirstRanker.com ---
? LCAT esterifies the Cholesteroland to HDL.
--- Content provided by FirstRanker.com ---
CETP(Cholesteryl Ester Transfer Protein)
Cholesterol Ester Transfer Protein
--- Content provided by FirstRanker.com ---
CETP
? CETP is also termed as plasma
--- Content provided by FirstRanker.com ---
lipid transfer protein.? CETP exchanges Lipids from
one Lipoprotein to another.
--- Content provided by FirstRanker.com ---
CETP Activity
? CETP is a Plasma Protein that
--- Content provided by FirstRanker.com ---
facilitates the transport of
? Cholesteryl Esters and
--- Content provided by FirstRanker.com ---
Triacylglycerol between the
Lipoproteins.
?By CETP activity
--- Content provided by FirstRanker.com ---
Cholesteryl Ester May be
transferred from HDL to:
--- Content provided by FirstRanker.com ---
? VLDL? IDL
? LDL
? CETP transfers TAG from VLDL or LDL
--- Content provided by FirstRanker.com ---
to HDL
? In exchange of Cholesteryl Esters
--- Content provided by FirstRanker.com ---
from HDL to VLDL.? HDL either transfers Cholesterol &
Cholesterol esters.
--- Content provided by FirstRanker.com ---
? To Liver by means of CETPCETP by its activity
Transforms HDL
--- Content provided by FirstRanker.com ---
HDL 3 to HDL 2
Sub fractions Of HDL
HDL2 and HDL3
--- Content provided by FirstRanker.com ---
?Prior to CETP activity HDL is
smaller particles termed as
--- Content provided by FirstRanker.com ---
HDL3? Post CETP activity HDL3
become larger TAG rich and
--- Content provided by FirstRanker.com ---
termed as HDL2
?HDL 3 is Cholesteryl
Ester rich biomolecule.
--- Content provided by FirstRanker.com ---
?HDL 2 is TAG and CE
containing.
--- Content provided by FirstRanker.com ---
? The receptors present onHepatocytes are for HDL 2.
? HDL 2 is internalized in the
--- Content provided by FirstRanker.com ---
hepatocytes and get
metabolized.
Significance Of CETP Activity
--- Content provided by FirstRanker.com ---
? Significance of CETP activity is to
transfer
--- Content provided by FirstRanker.com ---
? The valuable functional compoundCholesterol from HDL to VLDL and get
transported to extrahepatocytes when
--- Content provided by FirstRanker.com ---
it is required for its use.
? Hence CETP activity is induced when
--- Content provided by FirstRanker.com ---
there is need of Cholesterol toExtrahepatocytes.
?CETP activity reduces the
--- Content provided by FirstRanker.com ---
content of CholesterylEster of HDL.
--- Content provided by FirstRanker.com ---
? Low CE content of HDL after
CETP activity
--- Content provided by FirstRanker.com ---
? Increases the HDL associatedLCAT activity.
--- Content provided by FirstRanker.com ---
Inhibition Of CETP Activity
Causes High HDL levels In
--- Content provided by FirstRanker.com ---
Blood Circulation
? Inhibition of CETP will not transfer the HDL
Cholesteryl Ester to VLDL, for use in extra
--- Content provided by FirstRanker.com ---
hepatocytes.
? Not modify HDL3 to HDL2
? No internalization of HDL3 by hepatocytes.
--- Content provided by FirstRanker.com ---
? This may elevate the levels of HDL3 in blood.? Defective Scavenging role of HDL
? This leading to its bad consequences of
Atherosclerosis.
--- Content provided by FirstRanker.com ---
? Inhibition of CETP increases HDL3
levels.
--- Content provided by FirstRanker.com ---
? But highly reduced CETP activityaccelerates very high HDL3 levels.
? This abnormal high levels of HDL3
--- Content provided by FirstRanker.com ---
evidenced showing development of
Atherosclerosis and Coronary Heart
--- Content provided by FirstRanker.com ---
Diseases.?Recent Studies have
--- Content provided by FirstRanker.com ---
evidenced?The CETP inhibiting drugs
?Elevates the levels of HDL3
--- Content provided by FirstRanker.com ---
and?Increases the mortality
rate.
--- Content provided by FirstRanker.com ---
ApolipoproteinsFunctions of
Apolipoproteins
--- Content provided by FirstRanker.com ---
? Apoproteins are protein parts ofLipoprotein structure
? Apoproteins act as structural
--- Content provided by FirstRanker.com ---
components of Lipoproteins?Apoproteins are polar moieties
which impart solubility to
--- Content provided by FirstRanker.com ---
Lipoprotein structure.? Apoproteins
? Recognizes the Lipoprotein
--- Content provided by FirstRanker.com ---
receptors on cell membrane
surface as ligand.
--- Content provided by FirstRanker.com ---
? Which further facilitates theuptake of LP by specific
tissues.
--- Content provided by FirstRanker.com ---
Apoproteins Activate /InhibitEnzymes Involved
in Lipoprotein metabolism.
--- Content provided by FirstRanker.com ---
v Apo A I: Activator LCAT
v Apo C-I : Activator of LCAT
v Apo A-IV: Activator of LCAT
--- Content provided by FirstRanker.com ---
? Apo C-II: Activator of LPL? Apo C-III: Inhibitor of LPL
? Apo AII: Inhibitor of Hepatic Lipase (HL)
--- Content provided by FirstRanker.com ---
? Chylomicrons contain ApoB-48.
? VLDLs, IDLs and LDLs has ApoB-100.
HDL transfers
--- Content provided by FirstRanker.com ---
Apo E & Apo CII
to
--- Content provided by FirstRanker.com ---
Chylomicrons & VLDLChylomicron
Metabolism
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
Metabolism of Chylomicrons
Surface Monolayer
--- Content provided by FirstRanker.com ---
PhospholipidsFree Cholesterol
Protein
--- Content provided by FirstRanker.com ---
Hydrophobic Core
Triglyceride
--- Content provided by FirstRanker.com ---
Cholesteryl EstersChylomicrons
? Assembled in intestinal mucosal
--- Content provided by FirstRanker.com ---
cel s
? Has lowest density
? It has largest size
--- Content provided by FirstRanker.com ---
? Highest % of lipids and lowest %proteins
? Highest concentration of
--- Content provided by FirstRanker.com ---
Triacylglycerol (dietary origin)? Chylomicrons carry dietary lipids
from intestine to Liver
--- Content provided by FirstRanker.com ---
? Responsible for physiological milky
appearance of plasma (up to 2
--- Content provided by FirstRanker.com ---
hours after meal)? Chylomicron is a type of
Lipoprotein
--- Content provided by FirstRanker.com ---
? Formed in the intestinal
mucosal cells
--- Content provided by FirstRanker.com ---
? Due to aggregation ofdietary digested and
absorbed Lipids.
--- Content provided by FirstRanker.com ---
? The Chylomicrons has 99%Lipids and 1% Proteins
? The predominant Lipid present
--- Content provided by FirstRanker.com ---
in Chylomicrons is
Triacylglycerol (TAG) of dietary
--- Content provided by FirstRanker.com ---
origin.? The Apoprotein of Chylomicron is
B48
--- Content provided by FirstRanker.com ---
? Significant role of Chylomicron is
to transport dietary Lipids from
--- Content provided by FirstRanker.com ---
intestinal mucosal cell to Liver viaLymph and Blood.
? Chylomicrons formed in
--- Content provided by FirstRanker.com ---
intestinal mucosal cells are? First released in lymphatic
system
--- Content provided by FirstRanker.com ---
? Which then enters systemic
blood circulation via thoracic
--- Content provided by FirstRanker.com ---
duct.? Chylomicrons in blood circulation are not
moved inertly
--- Content provided by FirstRanker.com ---
? But receives Apo C I and Apo E from the
circulating HDL and gets mature.
--- Content provided by FirstRanker.com ---
? Apo C I then stimulates the enzymeLipoprotein Lipase present in endothelial
lining of blood vessels of Adipose tissue
--- Content provided by FirstRanker.com ---
and Cardiac tissue.
? The stimulated Lipoprotein Lipase acts
upon TAG of Chylomicrons ,
--- Content provided by FirstRanker.com ---
? Hydrolyze it into free fatty acids and
Glycerol ,which then enters to
--- Content provided by FirstRanker.com ---
adjacent adiposecytes.? Entered Free fatty acids TAG and
stored as reserve food material.
--- Content provided by FirstRanker.com ---
? The circulating Chylomicrons
are continuously acted upon by
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase? Most of the TAG is removed
from it and transformed to
--- Content provided by FirstRanker.com ---
Chylomicron remnant till they
reach Liver.
? The Liver has receptors for
--- Content provided by FirstRanker.com ---
Chylomicron remnant.
? Chylomicron remnant linked to
--- Content provided by FirstRanker.com ---
receptors of hepatocytes areinternalized and metabolized in
Liver.
--- Content provided by FirstRanker.com ---
? Chylomicrons transport dietary TAG
--- Content provided by FirstRanker.com ---
and Cholesterol from the intestine tothe peripheral tissues
? Lipoprotein lipase (LPL) is
--- Content provided by FirstRanker.com ---
activated by Apo C-II? After most of the TG is removed,
Chylomicrons become
--- Content provided by FirstRanker.com ---
Chylomicron remnants. During
the process, CM give ApoC and
--- Content provided by FirstRanker.com ---
ApoA back to HDL?CM remnants bind to specific
receptors on the surface of liver
--- Content provided by FirstRanker.com ---
cells through apo E and then the
complex is Endocytosed.
--- Content provided by FirstRanker.com ---
?Remnant receptor or ApoEreceptor or LRP (LDL receptor-
related protein)
--- Content provided by FirstRanker.com ---
? Chylomicron remnants deliver
dietary cholesterol and some
--- Content provided by FirstRanker.com ---
cellular cholesterol (via HDL)to the liver.
? Half life of CM is short, less
--- Content provided by FirstRanker.com ---
than 1 hour.
Chylomicrons
--- Content provided by FirstRanker.com ---
Nascent Chylomicron are formed in the intestinal and
consists of rich in dietary TG + minimal amount of
--- Content provided by FirstRanker.com ---
dietary cholesterol + Apo (B-48)Mature Chylomicron after Nascent chylomicron
passage to blood, addition of Apo C II and Apo E from
--- Content provided by FirstRanker.com ---
HDL
Lipoprotein lipase hydrolyzes TAG present in
--- Content provided by FirstRanker.com ---
ChylomicronsChylomicron remnant taken up by the liver through
endocytosis.
--- Content provided by FirstRanker.com ---
Apo C removed and returns back to HDL
Metabolic fate of chylomicrons. (A, apolipoprotein A; B-48, apolipoprotein B-48; , apolipoprotein C; E, apolipoprotein E;
--- Content provided by FirstRanker.com ---
HDL, high-density lipoprotein; TG, triacylglycerol; C, cholesterol and cholesteryl ester; P, phospholipid; HL, hepatic lipase; LRP,LDL receptor-related protein.) Only the predominant lipids are shown.
--- Content provided by FirstRanker.com ---
Metabolism of VLDL and LDLFormation and Fate Of VLDL
? The Lipoprotein Very Low
--- Content provided by FirstRanker.com ---
Density Lipoprotein (VLDL)? Biosynthesized in
Hepatocytes and Intestinal
--- Content provided by FirstRanker.com ---
Mucosal Cells.
?The endogenously
--- Content provided by FirstRanker.com ---
biosynthesized Lipids areaggregated
?Along with Apoprotein B-
--- Content provided by FirstRanker.com ---
100 to form VLDL.
? VLDL predominantly
contains Triacylglycerol of
--- Content provided by FirstRanker.com ---
endogenous origin.
Role Of VLDL
--- Content provided by FirstRanker.com ---
? VLDL facilitates in mobilizing out theendogenously synthesized Lipids in
Hepatocytes and Intestinal mucosal cells.
--- Content provided by FirstRanker.com ---
? VLDL transports endogenous Lipids
from Liver to Extra Hepatocytes via
--- Content provided by FirstRanker.com ---
blood.?Nascent VLDL accepts Apo
CII and Apo E from HDL
--- Content provided by FirstRanker.com ---
?This modify it to matureVLDLs in blood.
? Nascent VLDL: contains Apo B-100
--- Content provided by FirstRanker.com ---
? Mature VLDL: Apo B-100 plusApo C-II and Apo E
(from HDL)
--- Content provided by FirstRanker.com ---
? Apo C-I is required for activation ofLipoprotein lipase
? Lipoprotein lipase is required to
--- Content provided by FirstRanker.com ---
degrade VLDL TAG into Glycerol and
fatty acids
--- Content provided by FirstRanker.com ---
?Circulating VLDL onaction by Lipoprotein
Lipase hydrolyzes most
--- Content provided by FirstRanker.com ---
of its TAG.
?VLDL gets modified to
--- Content provided by FirstRanker.com ---
IDL and LDL.? Thus intermediate product of
IDL and end product LDL are
--- Content provided by FirstRanker.com ---
formed from VLDL? In blood circulation by action
of LPL on VLDL and removal of
--- Content provided by FirstRanker.com ---
TAG from it.
Normal VLDL Metabolism
--- Content provided by FirstRanker.com ---
Prevents the personto
Suffer from Fatty Liver
--- Content provided by FirstRanker.com ---
? VLDL help in mobilizing out theendogenously biosynthesized Lipids
of Hepatocytes.
--- Content provided by FirstRanker.com ---
? Normal Formation and mobilization
of VLDL prevents from accumulation
--- Content provided by FirstRanker.com ---
of excess Fat in the Liver anddevelop Fatty Liver.
Modifications of Circulating VLDLs
--- Content provided by FirstRanker.com ---
VLDL IDL (returns Apo E to HDL) LDL
VLDL Metabolism
--- Content provided by FirstRanker.com ---
Dietary Carbohydrate Increases
VLDL Production
--- Content provided by FirstRanker.com ---
PlasmaTriglyceride
Dietary
--- Content provided by FirstRanker.com ---
(VLDL)
Carbohydrate
--- Content provided by FirstRanker.com ---
VLDL Remnants
IDL and LDL
--- Content provided by FirstRanker.com ---
? LDL results from loss of TAG inVLDL
? LDL contains relatively more
--- Content provided by FirstRanker.com ---
Cholesterol esters
? LDL looses all Apo lipoproteins
--- Content provided by FirstRanker.com ---
except ApoB100.Very Low Density Lipoprotein (VLDL)
--- Content provided by FirstRanker.com ---
Nascent VLDLare formed in the liver and consists ofendogenous TG + 17 % cholesterol + Apo (B-100)
Mature VLDL after Nascent VLDL passage to
--- Content provided by FirstRanker.com ---
blood, addition of ApoC II, ApoE and cholesterol
esters from HDL
--- Content provided by FirstRanker.com ---
Lipoprotein lipase (LPL) hydrolyzes TAG presentin VLDL
VLDL remnant containing less of TG and more of
--- Content provided by FirstRanker.com ---
cholesterol and taken up by the liver through
endocytosis.
--- Content provided by FirstRanker.com ---
Apo C removed and returns to HDLLDL Metabolism
Most core lipid in LDL is Cholesterol ester.
--- Content provided by FirstRanker.com ---
ApoB100 is only Apolipoprotein in the surface.Formation and Fate Of LDL
? Low Density Lipoprotein (LDL) is a
--- Content provided by FirstRanker.com ---
Lipoprotein formed from VLDL inblood circulation.
? VLDL in blood circulation
--- Content provided by FirstRanker.com ---
receives Apo CII and Apo E from
the circulating HDL.
? Apo CI then stimulates the
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase enzyme
present in the endothelial lining
--- Content provided by FirstRanker.com ---
of blood vessels.? Lipoprotein Lipase then acts upon
TAG present in VLDL ,hydrolyze it
--- Content provided by FirstRanker.com ---
to Glycerol and free fatty acids
?LDL is the modified
form of VLDL formed
--- Content provided by FirstRanker.com ---
in blood circulation.
?LDL is remnant of
--- Content provided by FirstRanker.com ---
VLDL?LDL is mostly associated
with Cholesterol and
--- Content provided by FirstRanker.com ---
Phospholipids with
minimal TAG
--- Content provided by FirstRanker.com ---
?Of endogenous originmobilized out from Liver.
? The major Apoproteins of LDL
--- Content provided by FirstRanker.com ---
is Apo B100? Same as VLDL since LDL is
derived from VLDL
--- Content provided by FirstRanker.com ---
? Function of LDL is to transport
endogenously biosynthesized
--- Content provided by FirstRanker.com ---
Cholesterol from Liver to theperipheral /extrahepatic tissues.
LDL Receptor
--- Content provided by FirstRanker.com ---
?LDL receptor is also namedas ApoB100/ApoE
receptors
--- Content provided by FirstRanker.com ---
?Since ApoB-100 of LDL
binds to LDL receptor.
--- Content provided by FirstRanker.com ---
?The complexes of LDL andreceptor are taken into the
cells by endocytosis,
--- Content provided by FirstRanker.com ---
?Where LDL is degraded but
the receptors are recycled
? LDL receptors are found on cel
--- Content provided by FirstRanker.com ---
surface of many cel types of
extrahepatocytes.
--- Content provided by FirstRanker.com ---
? LDL is internalized by the tissueswhen LDL get fixed to the LDL
receptors.
--- Content provided by FirstRanker.com ---
? LDL receptor mediates
delivery of Cholesterol
--- Content provided by FirstRanker.com ---
? By inducing endocytosisand fusion with Lysosomes.
--- Content provided by FirstRanker.com ---
? Lysosomal lipases andproteases degrade the LDL.
--- Content provided by FirstRanker.com ---
? Cholesterol then incorporatesinto cell membranes or is
stored as cholesterol-esters of
--- Content provided by FirstRanker.com ---
extrahepatocytes.
LDL Receptor
--- Content provided by FirstRanker.com ---
LDL Cholesterol levels
are
--- Content provided by FirstRanker.com ---
positively related to riskof Cardiovascular
Disease.
--- Content provided by FirstRanker.com ---
?LDL values withinnormal range is an
indication of healthy
--- Content provided by FirstRanker.com ---
status.
?But the high LDL levels
--- Content provided by FirstRanker.com ---
are abnormal .? The Cholesterol associated to
this high levels of LDL
--- Content provided by FirstRanker.com ---
molecules increases the risk of
Atherosclerosis and CVD.
--- Content provided by FirstRanker.com ---
? Hence this LDL associated
Cholesterol is termed as "bad
--- Content provided by FirstRanker.com ---
Cholesterol"Defect/Absence of
LDL Receptors
--- Content provided by FirstRanker.com ---
Leads to Accumulation of LDLin Blood Circulation
Causing
--- Content provided by FirstRanker.com ---
Hypercholesteremia
and
--- Content provided by FirstRanker.com ---
Atherosclerosis? Defect in LDL receptors on tissues
impairs LDL metabolism.
--- Content provided by FirstRanker.com ---
? Decreases LDL internalization
within the tissues.
--- Content provided by FirstRanker.com ---
? Increases abnormal levels of LDL inblood (< 130 mg%).
? Increased LDL levels in
--- Content provided by FirstRanker.com ---
blood circulation due todefect in LDL receptors is
termed as Type I a
--- Content provided by FirstRanker.com ---
Hyperlipoproteinemia.
? The major form of Lipid associated with LDL
--- Content provided by FirstRanker.com ---
is Cholesterol .? Hence increased LDL levels is characterized
by Hypercholesterolemia.
--- Content provided by FirstRanker.com ---
? The Cholesterol associated with elevated
levels of LDL (more than its normal range) is
--- Content provided by FirstRanker.com ---
termed as bad Cholesterol,? Since it increases the risk of Atherosclerosis
and its complications .
--- Content provided by FirstRanker.com ---
? Persons lacking the LDLreceptor suffer from Familial
Hypercholesteremia
--- Content provided by FirstRanker.com ---
? Due to result of a mutation in
a single autosomal gene
--- Content provided by FirstRanker.com ---
? Total plasma cholesterol andLDL levels are elevated.
?Cholesterol Levels of:
--- Content provided by FirstRanker.com ---
?Healthy person = < 200 mg/dl
?Heterozygous individuals = 300 mg/dl
--- Content provided by FirstRanker.com ---
?Homozygous individuals = 680 mg/dl
--- Content provided by FirstRanker.com ---
High LDL levels can lead toCardiovascular Disease
Most Homozygous individuals
--- Content provided by FirstRanker.com ---
die of cardiovascular disease
in childhood
? LDL can be oxidized to form
--- Content provided by FirstRanker.com ---
oxidized LDL
? Oxidized LDL is taken up by
--- Content provided by FirstRanker.com ---
immune cells cal edmacrophages.
? Macrophages become
--- Content provided by FirstRanker.com ---
engorged to form foam cells.
? Foam cel s become trapped in
--- Content provided by FirstRanker.com ---
the wal s of blood vessels andcontribute to the formation of
atherosclerotic plaques.
--- Content provided by FirstRanker.com ---
? Causes narrowing of the
arteries which can lead to
--- Content provided by FirstRanker.com ---
MI/heart attacks.Familial hypercholesterolemia is due to a gene
--- Content provided by FirstRanker.com ---
defect in the LDL receptor? Michael Palmer 2014
Role Of HDL
--- Content provided by FirstRanker.com ---
Reverse Transport OfCholesterol
?HDL is a high density
--- Content provided by FirstRanker.com ---
Lipoprotein.
?Nascent HDL is
--- Content provided by FirstRanker.com ---
biosynthesized in Liver.? HDL is the Lipoprotein, with highest
density.
--- Content provided by FirstRanker.com ---
? Since it is associated with 40-50% ofApoproteins.
? The Apoproteins of HDL are Apo A I,
--- Content provided by FirstRanker.com ---
Apo A I , Apo C I,C I , Apo D and Apo E.
? HDL serves as a reservoir of
--- Content provided by FirstRanker.com ---
Apoprotein during its circulation.? HDL gives it Apo CII and Apo E to
circulating nascent Chylomicrons
--- Content provided by FirstRanker.com ---
and VLDL .
? Nascent HDL of discoid shaped
(Empty Bag) biosynthesized in
--- Content provided by FirstRanker.com ---
Liver
? It is released in the blood
--- Content provided by FirstRanker.com ---
circulation for scavenging action.The HDL has Scavenging Action
It serves as a
--- Content provided by FirstRanker.com ---
Scavenger For
Unwanted Body Lipids
? The Enzyme Lecithin Cholesterol Acyl
--- Content provided by FirstRanker.com ---
Transferase (LCAT) is associated with HDL
metabolism.
--- Content provided by FirstRanker.com ---
? Apo A I,A IV and CI stimulates the LCATactivity of HDL.
? LCAT by its activity help in esterification of
--- Content provided by FirstRanker.com ---
free Cholesterol to Esterified
Cholesterol/Cholesterol Ester.
--- Content provided by FirstRanker.com ---
? HDL by its scavenging action collects the extranon functional Cholesterol lying in blood
vessels and peripheral tissues.
--- Content provided by FirstRanker.com ---
? HDL esterifies Choleserol by its LCAT activity
and to HDL bag.
--- Content provided by FirstRanker.com ---
? The nascent HDL bags changes to sphericalshape .
? HDL is more associated with Phospholipids
--- Content provided by FirstRanker.com ---
and Cholesterol.
? The receptors for HDL are
present on Liver cells.
--- Content provided by FirstRanker.com ---
? HDL transports the excess,
unused Lipids from extra
--- Content provided by FirstRanker.com ---
hepatic tissues back to Liver forits metabolism and excretion.
? The role of HDL is opposite to LDL.
--- Content provided by FirstRanker.com ---
? HDL transports Cholesterol From
extra hepatic tissues back to Liver.
--- Content provided by FirstRanker.com ---
? Thus the role of HDL is termed asreverse transport of Cholesterol.
? Normal serum HDL levels are 30-60
--- Content provided by FirstRanker.com ---
mg%.? The efficient activity of HDL is good
to the body
--- Content provided by FirstRanker.com ---
? As it prevents risk of Atherosclerosis
and their complications.
--- Content provided by FirstRanker.com ---
Reverse Cholesterol Transport (RCT)High Density Lipoproteins (HDL ? Good)
--- Content provided by FirstRanker.com ---
? CETP by its activity modifies HDL 3to HDL 2.
? HDL2 is then get internalized in
--- Content provided by FirstRanker.com ---
Hepatocytes for its final use.
? Cholesterol Ester carried by HDL to
--- Content provided by FirstRanker.com ---
hepatocytes is degraded to Bileacids and Bile salts and get excreted
out.
--- Content provided by FirstRanker.com ---
Fate of HDLHDL 2 binds SR-B1 receptor on Hepatocytes
Transfers Cholesterol &
--- Content provided by FirstRanker.com ---
Cholesterol ester to cell
Depleted HDL dissociates
--- Content provided by FirstRanker.com ---
& re-enters circulation? HDL can bind to specific
hepatic receptors SR-B1
--- Content provided by FirstRanker.com ---
? But primary HDL clearance
occurs through uptake by
--- Content provided by FirstRanker.com ---
scavenger receptor SR-B1.? SR-B1 can be upregulated in cells
when Cholesterol levels are low in
--- Content provided by FirstRanker.com ---
hepatic cells.? SR-B1 is down regulated when
cholesterol levels are high in cells.
--- Content provided by FirstRanker.com ---
? Defect in low HDL synthesis in Liver
lowers the HDL activity and increases
--- Content provided by FirstRanker.com ---
the risk of Atherosclerosis.? Defect in HDL receptors on Liver may
abnormally increase the HDL levels in
--- Content provided by FirstRanker.com ---
blood circulation and also increases the
risk of Atherosclerosis.
The Lecithin-Cholesterol Acyltransferase (LCAT)
--- Content provided by FirstRanker.com ---
reaction
Cholesterol esters can be stored inside lipoprotein
--- Content provided by FirstRanker.com ---
particlesHDL Interactions
with Other Particles
--- Content provided by FirstRanker.com ---
Tangier Disease: Disruption of CholesterolTransfer to HDL
? Michael Palmer 2014
--- Content provided by FirstRanker.com ---
HDL and Reverse Cholesterol Transport
Tangier Disease
--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
LDL-R
--- Content provided by FirstRanker.com ---
LDL-R
--- Content provided by FirstRanker.com ---
50% of HDL C may
Return to the liver
--- Content provided by FirstRanker.com ---
On LDL via CETPLDL/HDL Ratio and Cardiovascular Disease
? LDL/HDL ratios are used as a
--- Content provided by FirstRanker.com ---
diagnostic tool for signs of
Cardiovascular disease
--- Content provided by FirstRanker.com ---
? A good LDL/HDL ratio is 3.5?LDL above normal range =
"Bad Cholesterol"
?HDL within normal range =
--- Content provided by FirstRanker.com ---
"Good Cholesterol"-HDL above normal range =
"Bad Cholesterol"
? Protective role of HDL is not very
--- Content provided by FirstRanker.com ---
clear.
?An esterase that breaks down
--- Content provided by FirstRanker.com ---
oxidized lipids is associated withHDL.
?It is possible (but not proven) that
--- Content provided by FirstRanker.com ---
this enzyme helps to destroy
oxidized LDL
--- Content provided by FirstRanker.com ---
Lipoproteins Facilitate Lipid
Transport
Normal
--- Content provided by FirstRanker.com ---
Lipoprotein Metabolism
Normal LP Metabolism
--- Content provided by FirstRanker.com ---
? Maintains Normal levels of Lipoproteinsin the blood circulation by:
?Normal Formation of LP by specific tissues
--- Content provided by FirstRanker.com ---
?Normal Transformation and Transport of
LP in blood
--- Content provided by FirstRanker.com ---
?Normal Uptake of LP by specific tissues? Normal Lipoprotein
Metabolism Reduces the risk
--- Content provided by FirstRanker.com ---
of:?Atherosclerosis
?Myocardial Infarction
--- Content provided by FirstRanker.com ---
?Stroke
Lipoprotein Population Distributions
--- Content provided by FirstRanker.com ---
? Serum Lipoproteinconcentrations differ between
adult men and women.
--- Content provided by FirstRanker.com ---
? Primarily as a result of
differences in sex hormone
--- Content provided by FirstRanker.com ---
levels.? Women having, on average, higher HDL
cholesterol levels and lower total
--- Content provided by FirstRanker.com ---
Cholesterol and TAG levels than men.? The difference in total cholesterol,
however, disappears in post
--- Content provided by FirstRanker.com ---
menopause as Estrogen decreases and
use of Cholesterol is reduced.
--- Content provided by FirstRanker.com ---
Lipid Associated DisordersOR
Lipid Related Clinical Problems
--- Content provided by FirstRanker.com ---
? DysLipoproteinemias/Dyslipidemias(Hypo and Hyperlipoproteinemias)
? Fatty Liver
--- Content provided by FirstRanker.com ---
?Atherosclerosis
?Coronary Heart Diseases
--- Content provided by FirstRanker.com ---
Causes of Lipid Associated Disorders? Diseases associated with abnormal lipid
concentrations can be caused:
--- Content provided by FirstRanker.com ---
?Nutritional Imbalances
?Environmental Factors
--- Content provided by FirstRanker.com ---
?Lifestyle Patterns?Genetic abnormalities
?Develop secondarily, as a
--- Content provided by FirstRanker.com ---
consequence of other diseases.
Disorders Of Lipoproteins
Dyslipoproteinemias/ Dyslipidemias
--- Content provided by FirstRanker.com ---
Hyperlipoproteinemias
And
--- Content provided by FirstRanker.com ---
HypolipoproteinemiasAbnormal LP Metabolism
? Abnormal Synthesis of LP by specific
--- Content provided by FirstRanker.com ---
tissues
? Abnormal Transport of LP in blood
? Abnormal Uptake by specific tissues
--- Content provided by FirstRanker.com ---
? Leads to abnormal levels of Lipoproteinsin the blood circulation
? Thus conditions and factors
--- Content provided by FirstRanker.com ---
which affects theLipoprotein synthesis,
transport and uptake
--- Content provided by FirstRanker.com ---
? May lead to Lipoprotein
disorders/Dyslipidemias.
--- Content provided by FirstRanker.com ---
Dyslipidemias? Dyslipidemias are due to Defect in
Lipoprotein metabolism
--- Content provided by FirstRanker.com ---
? Include both the excess and
deficiency of Lipoproteins.
--- Content provided by FirstRanker.com ---
? Dyslipidemia can manifest as theelevation of plasma Cholesterol,
Triacylglycerol, or both.
--- Content provided by FirstRanker.com ---
? It can also be manifested by:
?The elevation of LDL Cholesterol
?The abnormal decrease/increase
--- Content provided by FirstRanker.com ---
of HDL Cholesterol in the blood.
Causes Of Dyslipidemias/
--- Content provided by FirstRanker.com ---
DysLipoproteinemias? Dyslipedimias states are generally
caused by impaired Lipoprotein :
--- Content provided by FirstRanker.com ---
?Biosynthesis (Increased)
?Transformation and Transport
(Improper )
--- Content provided by FirstRanker.com ---
?Uptake and Utilization (Decreased)
Dyslipidemias/Dyslipoproteinemias
? Dyslipidemias can be subdivided into two
--- Content provided by FirstRanker.com ---
major categories
1. Hyperlipoproteinemias
--- Content provided by FirstRanker.com ---
? Hypercholesterolemia? Hypertriglyceridemia
? Combined Hyperlipoproteinemia
2. Hypolipoproteinemias
--- Content provided by FirstRanker.com ---
Types Of Lipoprotein Disorders
Hyperlipoproteinemias
? Hyperlipoproteinemia are
--- Content provided by FirstRanker.com ---
abnormal conditions
? With increased levels of
--- Content provided by FirstRanker.com ---
circulating Lipoproteins inthe blood.
Causes of Hyperlipoproteinemia
--- Content provided by FirstRanker.com ---
? Increased formation of Lipoprotein
? Reduced clearance of LP from circulation
? Factors Causing These
--- Content provided by FirstRanker.com ---
? Excessive dietary intake of Carbs and Lipids
? Biochemical defects in LP metabolism
? Deficient Protein to form Apo proteins
? Defect in Enzymes and Protein Associated to LP
--- Content provided by FirstRanker.com ---
? Defect in Receptors for LP? Use of drugs that perturb LP formation or
catabolism
Types of
--- Content provided by FirstRanker.com ---
Hyperlipoproteinemias
Fredrickson Classification
--- Content provided by FirstRanker.com ---
ofHyperlipoproteinemia
Type I
--- Content provided by FirstRanker.com ---
Lipoprotein Lipase DeficiencyIncreased Chylomicrons and
Hyperlipoproteinemia VLDL
--- Content provided by FirstRanker.com ---
Hypertriglyceridemia
Type II a Defect in LDL Receptors
--- Content provided by FirstRanker.com ---
Increased LDL levels in bloodHyperlipoproteinemia Hyperbetalipoproteinemia
Hypercholesterolemia
--- Content provided by FirstRanker.com ---
Type II b Increased production of Apo B
Increased production of
--- Content provided by FirstRanker.com ---
Hyperlipoproteinemia VLDL and impaired LDLcatabolism Increased VLDL and
LDL
--- Content provided by FirstRanker.com ---
Type I I
Defect in ApoE
--- Content provided by FirstRanker.com ---
Familial Dysbeta Broad Beta DiseaseLipoproteinemias Increased IDL
Type IV
--- Content provided by FirstRanker.com ---
Impaired VLDL metabolism.
Increased VLDL
--- Content provided by FirstRanker.com ---
Hyper-pre-b-Lipoproteinemia
Due to acquired conditions viz
--- Content provided by FirstRanker.com ---
q Obesity
q Alcoholism
--- Content provided by FirstRanker.com ---
q Diabetes mel itusIncreased VLDL and
--- Content provided by FirstRanker.com ---
ChylomicronsDue to acquired
Type V conditions viz
--- Content provided by FirstRanker.com ---
q Obesity
Combined
--- Content provided by FirstRanker.com ---
q AlcoholismHyperlipoproteinemia
q Diabetes mel itus
--- Content provided by FirstRanker.com ---
Conditions Of Hyperlipoproteinemias? Increased endogenous/exogenous
availability of Lipids
--- Content provided by FirstRanker.com ---
? Increased/Defective Apoprotein
synthesis
--- Content provided by FirstRanker.com ---
? Decreased Lipoprotein Lipase activity? Defective receptors on specific tissues
Deficiency Of Lipoprotein Lipase
--- Content provided by FirstRanker.com ---
Leads To
Familial Type I Hyperlipoproteinemia
? Defect in Lipoprotein Lipase activity
--- Content provided by FirstRanker.com ---
? Does not clear the circulatingChylomicrons and VLDL;
? Increases the levels of circulating
--- Content provided by FirstRanker.com ---
Chylomicrons and VLDL
? Associated Hypertriglyceridemia
? This is termed as Familial Type I
--- Content provided by FirstRanker.com ---
Hyperlipoproteinemia.
Type I Hyperlipoproteinemias
--- Content provided by FirstRanker.com ---
? Shows a dramatic accumulation (1000mg/dl) of Chylomicrons and VLDL in
plasma
--- Content provided by FirstRanker.com ---
? Usual y associated withacute abdomen due to
acute pancreatitis
--- Content provided by FirstRanker.com ---
? plasma TAG even in the
fasted state
--- Content provided by FirstRanker.com ---
Type I I Hyperlipoproteinemia? Familial dysbetalipoproteinemia
? Due to Apo E deficiency
? Associated with
--- Content provided by FirstRanker.com ---
Hypercholesterolemia &
premature Atherosclerosis
Hypolipoproteinemias
--- Content provided by FirstRanker.com ---
Hypolipoproteinemias
? Hypolipoproteinemias are
--- Content provided by FirstRanker.com ---
abnormal conditions? With decreased levels of
circulating Lipoproteins in
--- Content provided by FirstRanker.com ---
the blood.
Conditions Of Hypolipoproteinemias
? Decreased synthesis of
--- Content provided by FirstRanker.com ---
Lipoproteins
? Deficiency of Lipotropic factors
--- Content provided by FirstRanker.com ---
required for Lipoproteinbiosynthesis.
Types Of Hypolipoproteinemias
--- Content provided by FirstRanker.com ---
Familial Hypobetalipoproteinemia?Impairment in the
synthesis of Apo B
--- Content provided by FirstRanker.com ---
?Characterized with low
LDL levels.
--- Content provided by FirstRanker.com ---
Abeta Lipoproteinemia? Rare disorder
? No synthesis of Apo B (Total
--- Content provided by FirstRanker.com ---
Absence)
? Absence of LDL (Beta Lipoprotein) in
--- Content provided by FirstRanker.com ---
blood circulation? Defect in TAG-transfer protein
? Accumulation of TAG in liver
--- Content provided by FirstRanker.com ---
Familial Alpha Lipoprotein DeficiencyTangiers Disease
? Absence of HDL (Alpha Lipoprotein)
--- Content provided by FirstRanker.com ---
in blood
? Affects severely Reverse transport
--- Content provided by FirstRanker.com ---
of Cholesterol? Hypercholesterolemia
? Increased risk of Atherosclerosis and
--- Content provided by FirstRanker.com ---
its Complications.
Classification Of
--- Content provided by FirstRanker.com ---
DyslipidemiasBased On
Number Of Gene Involvement
--- Content provided by FirstRanker.com ---
Primary Hyperlipoproteinemia?Monogenic defect
?Polygenic Defect
--- Content provided by FirstRanker.com ---
Monogenic DisordersvFamilial Hypercholesterolemia
vHomozygous or Heterozygous
--- Content provided by FirstRanker.com ---
vDefect: inactive LDL receptorvFamilial Lipoprotein Lipase deficiency
vDefect: inactive lipoprotein lipase
--- Content provided by FirstRanker.com ---
vFamilial combined Hyperlipidemia
vDefect: Unknown
Polygenic/Multifactorial
--- Content provided by FirstRanker.com ---
? These are commonly
encountered
--- Content provided by FirstRanker.com ---
vHypercholesterolemiavHypertriglyceridemia
Secondary Hyperlipidemias
--- Content provided by FirstRanker.com ---
?Alcoholism?Diabetes mellitus
?Uremia
?Drugs; b blockers, oral contraceptives,
--- Content provided by FirstRanker.com ---
thiazide diuretics?Diseases: Hypothyroidism, Nephrotic
syndrome, Obstructive liver disease
--- Content provided by FirstRanker.com ---
Combined Hyperlipoproteinemia? Presence of elevated levels of both serum
Total Cholesterol and Triacylglycerols.
--- Content provided by FirstRanker.com ---
? Genetic form of this condition
?Familial Combined Hyperlipoproteinemia
--- Content provided by FirstRanker.com ---
(FCH)?Type V Hyperlipoproteinemia
? An accumulation of Cholesterol-rich VLDL
--- Content provided by FirstRanker.com ---
and Chylomicron remnants as a result of
defective catabolism of those particles
--- Content provided by FirstRanker.com ---
1389Diagnosis And Therapeutic
Strategy Of Dyslipidemias
--- Content provided by FirstRanker.com ---
A. Identify patients at risk1. Routine screening of Serum Lipid
profile
--- Content provided by FirstRanker.com ---
2. Assessment of contributing risk factorsB. Non-Pharmacologic therapy
1. Diet modification
--- Content provided by FirstRanker.com ---
2. Lifestyle modificationC. Pharmacologic therapy
? Lipids and lipoproteins are
--- Content provided by FirstRanker.com ---
important indicators of CHD risk,
? This is the major reason for their
--- Content provided by FirstRanker.com ---
measurement in research, as well
as in clinical practice.
Estimation Of Lipid Profile
--- Content provided by FirstRanker.com ---
? Serum Triacylglycerol
? Serum Total Cholesterol
? Serum VLDL
? Serum LDL Cholesterol
--- Content provided by FirstRanker.com ---
? Serum HDL CholesterolHypertriglyceridemia
? Serum Triacylglycerol
--- Content provided by FirstRanker.com ---
? Borderline = 150-200 mg/ dl
? High 200-500 mg/dl
? Very High > 500 mg/dl
--- Content provided by FirstRanker.com ---
? Familial Hypertriglyceridemia? Genetic
? Secondary Hypertriglyceridemia
--- Content provided by FirstRanker.com ---
? Hormonal imbalances
? Imbalance between synthesis and clearance of VLDL
1394
--- Content provided by FirstRanker.com ---
Hypertriglyceridemia? Generally caused by deficiency of LPL or
LPL cofactor.
--- Content provided by FirstRanker.com ---
? LPL hydrolyzes TAG in Chylomicrons and
VLDL
--- Content provided by FirstRanker.com ---
? Deficiency of LPL prevents processing andclearing of Lipoproteins.
? Elevated even with fasting condition.
--- Content provided by FirstRanker.com ---
1395
Hypercholesterolemia
--- Content provided by FirstRanker.com ---
? Familial Hypercholesterolemia (FH)?Homozygous rare 1/million
?Total cholesterol 800-1000 mg/dl
--- Content provided by FirstRanker.com ---
?Heart attack as early as teenage years?Heterozygous cholesterols 300-600
mg/dl
--- Content provided by FirstRanker.com ---
?Heart attacks 20-50 years
Hypercholesterolemia
? Familial hypercholesterolemia (FH)
--- Content provided by FirstRanker.com ---
?Primarily LDL elevations
?Synthesis is normal but decrease or lack
LDL receptors
--- Content provided by FirstRanker.com ---
?Therefore LDL builds-up in serum
?Since cells cannot acquire from LDL
increase internal synthesis
--- Content provided by FirstRanker.com ---
Lipid Profile and Lipoprotein Analyses
LDL Methods
? Friedewald Calculation
--- Content provided by FirstRanker.com ---
? VLDL is estimated as TAG/5
LDL = Total Cholesterol ? HDL ? TAG/5
--- Content provided by FirstRanker.com ---
Lipoprotein Assay Methods? Separate Lipoprotein Fractions By:
? Electrophoresis ? Agarose or Polyacrylamide
--- Content provided by FirstRanker.com ---
? Chromatographic? Precipitation
? Ultracentrifugation
? Immunochemical
Serum Triglycerides
--- Content provided by FirstRanker.com ---
Normal
? Less than 150 mg/dL
--- Content provided by FirstRanker.com ---
Borderline High? 150-199 mg/dL
High
--- Content provided by FirstRanker.com ---
? 200-499 mg/dL
Very High
--- Content provided by FirstRanker.com ---
? 500+ mg/dLSerum Total Cholesterol
Normal
--- Content provided by FirstRanker.com ---
?Less than 200 mg/dL
Borderline High
--- Content provided by FirstRanker.com ---
?200-239 mg/dLHigh
?240 mg/dL or higher
--- Content provided by FirstRanker.com ---
HDL CholesterolOptimal:
?60+ mg/dL for both males and females
--- Content provided by FirstRanker.com ---
At Risk for Heart Disease:
?Women: less than 50 mg/dL
--- Content provided by FirstRanker.com ---
?Men: less than 40 mg/dLLDL Cholesterol
Optimal
--- Content provided by FirstRanker.com ---
? Less than 100 mg/dL
Near or above Optimal
--- Content provided by FirstRanker.com ---
? 100-129 mg/dLBorderline High
?130-159 mg/dL
--- Content provided by FirstRanker.com ---
High
?160-189 mg/dL
--- Content provided by FirstRanker.com ---
Very High? 190+ mg/dL
Consequences Of
--- Content provided by FirstRanker.com ---
Dyslipoprotein Metabolism?Fatty Liver
?Atherosclerosis and
--- Content provided by FirstRanker.com ---
its ComplicationsRole Of Liver In Lipid Metabolism
? Liver is the Biochemical Factory of
--- Content provided by FirstRanker.com ---
Human Body.? Liver plays an important role in
Lipid metabolism.
--- Content provided by FirstRanker.com ---
? Major pathways of Lipid
metabolism are efficiently carried
--- Content provided by FirstRanker.com ---
out in Liver.Lipid Metabolism
At Liver
--- Content provided by FirstRanker.com ---
In Well Fed Condition? Liver in well fed condition efficiently carries
out various metabolic pathways of Lipid
--- Content provided by FirstRanker.com ---
Metabolism.
?De Novo biosynthesis of Fatty acids
?Triacylglycerol Biosynthesis
--- Content provided by FirstRanker.com ---
?Cholesterol Biosynthesis?Phospholipid Biosynthesis
?Glycolipid Biosynthesis
?VLDL Biosynthesis
Lipid Metabolism
--- Content provided by FirstRanker.com ---
At Liver
In Emergency Condition
--- Content provided by FirstRanker.com ---
? Liver in emergency condition carriesfollowing metabolic pathways of
Lipid metabolism efficiently:
--- Content provided by FirstRanker.com ---
?Beta Oxidation of Fatty acids
?Ketogenesis
?Bile Acid and Bile Salt Formation
Fatty Liver
--- Content provided by FirstRanker.com ---
? Though Liver is the predominant
site for Lipid biosynthesis.
--- Content provided by FirstRanker.com ---
? Liver is not the storage organ forLipids.
?Normally 3-5% of Lipids are
--- Content provided by FirstRanker.com ---
present in Hepatocytes.? Endogenously biosynthesized
Lipids in Liver are
--- Content provided by FirstRanker.com ---
? Mobilized out in the form of
VLDL molecule.
? Efficient formation of VLDL
--- Content provided by FirstRanker.com ---
in Liver
? Does not al ow the excess
--- Content provided by FirstRanker.com ---
of Lipids to remain in Livertissue.
Fatty Liver/
--- Content provided by FirstRanker.com ---
Fatty Liver Disease/
Hepatosteatosis
What Is Fatty Liver?
--- Content provided by FirstRanker.com ---
? Fatty Liver is an abnormal
condition
--- Content provided by FirstRanker.com ---
? Where there is more than 5% ofLipids retained in Hepatocytes.
What Is Fatty Liver Disease?
--- Content provided by FirstRanker.com ---
? Fatty Liver disease (FLD), is a reversible
condition of Liver
--- Content provided by FirstRanker.com ---
? Wherein large vacuoles of Lipidsaccumulate in Liver cel s
? Via the process of Steatosis (Abnormal
--- Content provided by FirstRanker.com ---
retention of Lipids within a cell)
What Is Steatohepatitis ?
? Progressive inflammation of the
--- Content provided by FirstRanker.com ---
Liver (Hepatitis),
? Due to abnormal accumulation of
--- Content provided by FirstRanker.com ---
Lipids(Steatosis) is termed asHepatosteatosis/Steatohepatitis
.
--- Content provided by FirstRanker.com ---
Causes Of Fatty Liver
Clinical Conditions
Leading To Fatty Liver
--- Content provided by FirstRanker.com ---
OR
Risks For Developing Fatty Liver
--- Content provided by FirstRanker.com ---
?Defect in Hepatic?Biosynthesis of Lipids
?No Mobilization of
--- Content provided by FirstRanker.com ---
Endogenously
biosynthesized Lipids in
--- Content provided by FirstRanker.com ---
Liver?Accumulates Lipids in Liver
? Increased biosynthesis of Lipids than
--- Content provided by FirstRanker.com ---
the mobilization capacity ,due toincreased Carbohydrates.
? Decreased mobilization of Lipids
--- Content provided by FirstRanker.com ---
from Liver cells due to decreased
VLDL formation.
--- Content provided by FirstRanker.com ---
?Deficiency of Lipotropicfactors affects
?The VLDL formation and
--- Content provided by FirstRanker.com ---
mobilization of Lipids
out of Hepatocytes.
Conditions Leading To Fatty Liver
--- Content provided by FirstRanker.com ---
? Metabolic Syndrome
?Obesity
?Hypertension
--- Content provided by FirstRanker.com ---
?Dyslipidemias?Diabetes mel itus
? Alcoholism
? Malnutrition
--- Content provided by FirstRanker.com ---
(Deficiency of Lipotropic Factors)? Wilsons Disease
? Hepatitis A
? Hepatitis C
--- Content provided by FirstRanker.com ---
? Hepatotoxic Drugs : MTX, VA,Acetaminophen, TC, Tamoxifen,
Nefidepine, Amiodarone, CCl4 etc
--- Content provided by FirstRanker.com ---
Lipotropic Factors and Their Role
Adequate Presence of
Lipotropic factor
--- Content provided by FirstRanker.com ---
Prevents Retention of Lipids
in Liver
--- Content provided by FirstRanker.com ---
There by preventing Fatty Liver.? Lipotropic Factors are chemical
substances which helps in
--- Content provided by FirstRanker.com ---
formation of Phospholipids.
? This in turn helps in proper
--- Content provided by FirstRanker.com ---
formation and mobilization ofVLDL out from Liver.
Names Of Lipotropic Factors
--- Content provided by FirstRanker.com ---
? Lipotropic Factors are chemicalsinvolved in biosynthesis of
Phospholipids:
--- Content provided by FirstRanker.com ---
?Choline
?Betaine forms Choline
?Inositol
--- Content provided by FirstRanker.com ---
Amino Acids As Lipotropic Agents?Glycine
?Serine
?Methionine
--- Content provided by FirstRanker.com ---
Vitamins As Lipotropic Factors?Vitamin B 12
?Folic Acid
--- Content provided by FirstRanker.com ---
Types Of Fatty Liver4 Types Of Fatty Liver
? Alcoholic Fatty Liver
--- Content provided by FirstRanker.com ---
? Non Alcoholic Fatty Liver Disease (NAFLD)? Non Alcoholic Steatohepatitis (NASH)
? Acute Fatty Liver of Pregnancy
--- Content provided by FirstRanker.com ---
Consequences Of Fatty Liver
? Fatty liver is a reversible condition
and usual y goes away on its own.
--- Content provided by FirstRanker.com ---
? Generally Fatty liver often has no
symptoms and
--- Content provided by FirstRanker.com ---
? Does not cause any permanentdamage.
Consequences Of Fatty Liver
--- Content provided by FirstRanker.com ---
? Constant accumulation ofabnormal excess amount of
Lipids in Hepatocytes
--- Content provided by FirstRanker.com ---
? Affects the normal Liver
functions
--- Content provided by FirstRanker.com ---
? Leads to Parenchymal damageto Liver Tissues
? Causes Liver Cirrhosis.
--- Content provided by FirstRanker.com ---
? Excess of Lipids deposition in Hepatocytes
? Interferes the biochemical functions
? Brings inflammation of Liver (Hepatitis)
? Changes the cytological features
--- Content provided by FirstRanker.com ---
? Damages the cell components? Causes Liver Fibrosis
? Leads to Liver Cirrhosis
? Liver Carcinoma
Natural History of Fatty Liver Disease
--- Content provided by FirstRanker.com ---
Fatty liver
Steatohepatitis
--- Content provided by FirstRanker.com ---
Steatohepatitis + Fibrosis (First Stage of Scar)Steatohepatitis + Cirrhosis
--- Content provided by FirstRanker.com ---
Cryptogenic Cirrhosis
When there is repeated damage to
--- Content provided by FirstRanker.com ---
the LiverPermanent scarring of Hepatocytes
takes place
--- Content provided by FirstRanker.com ---
This is cal ed Liver Cirrhosis
Diagnostic Features
--- Content provided by FirstRanker.com ---
OF
Fatty Liver Disease
--- Content provided by FirstRanker.com ---
Laboratory AbnormalitiesIn Fatty Liver Disease
? 2 - 4 fold ALT &
--- Content provided by FirstRanker.com ---
? Normal Albumin. PT
AST
--- Content provided by FirstRanker.com ---
? Low ANA + < 1 in 320? AST: ALT Ratio < 1
? Serum Ferritin
--- Content provided by FirstRanker.com ---
? ALP slight in 1/3
? Iron saturation
--- Content provided by FirstRanker.com ---
? Dyslipidemia - TAG ? AST: ALT Ratio > 1? FBG and PPBG
if Cirrhosis sets in
--- Content provided by FirstRanker.com ---
? BUN & Creatinine - N
Fatty liver Normal liver
--- Content provided by FirstRanker.com ---
Features Of Normal Arterial Wal? The lumen of healthy arterial wal is
lined by:
--- Content provided by FirstRanker.com ---
?Confluent layer of Endothelial cel s
Features of Normal Endothelium
--- Content provided by FirstRanker.com ---
Controls Important function OfArterial wal
vNormal healthy arterial endothelium,
--- Content provided by FirstRanker.com ---
vRepels cells and inhibits blood clotting.
vHealthy arteries are soft and Elastic.
--- Content provided by FirstRanker.com ---
vNormal Endothelium- Regulates tissue andorgan blood flow.
vThe ability of blood vessels to dilate-
--- Content provided by FirstRanker.com ---
vasodilatation
vThe ability of blood vessels to constrict-
--- Content provided by FirstRanker.com ---
vasoconstrictionArteriosclerosis
What Is Arteriosclerosis?
--- Content provided by FirstRanker.com ---
? Arteriosclerosis is non-specific term usedto describe hardening and thickening of
the wal of arterioles.
--- Content provided by FirstRanker.com ---
OR
? Arteriosclerosis is a general term
--- Content provided by FirstRanker.com ---
describing any hardening (and loss ofelasticity) of medium or large arteries.
What Is Atherosclerosis?
--- Content provided by FirstRanker.com ---
? The term Atherosclerosis, comesfrom the Greek words
?Atheros- meaning "gruel" or
--- Content provided by FirstRanker.com ---
"paste"
?Sclerosis- meaning "hardness".
--- Content provided by FirstRanker.com ---
Atherosclerosisis a form of
Arteriosclerosis
--- Content provided by FirstRanker.com ---
Terms For Atherosclerosis? There are many terms associated
to Atherosclerosis including:
--- Content provided by FirstRanker.com ---
vAtheroma
v Fibrous Plaques
v Fibro Fatty Lesions
vAtherosclerotic Plaques
--- Content provided by FirstRanker.com ---
? Atherosclerosis are abnormal
Diseased/defective arteries.
--- Content provided by FirstRanker.com ---
?Arteries becomes hard and non elastic?Arteries are less or non Functional
?Arteries obstruct the normal blood
--- Content provided by FirstRanker.com ---
flow to cells/tissues/organs.
Atherosclerosis is
Hardening of Blood Vessels
--- Content provided by FirstRanker.com ---
due to formation of
Fibro Inflammatory Fatty Lesions/Plaques
--- Content provided by FirstRanker.com ---
? Atherosclerotic Plaque ResultsFrom Accumulation of :
?Lipids
--- Content provided by FirstRanker.com ---
?Connective tissue
?Inflammatory cells
--- Content provided by FirstRanker.com ---
?Smooth Muscle cells? In the intima of blood vessels.
Causes Of Atherosclerosis
--- Content provided by FirstRanker.com ---
Risk Factors For Atherosclerosis? Risk factors which accelerate the
progression of Atherosclerosis
--- Content provided by FirstRanker.com ---
and endothelial dysfunction are:
?Dyslipidemias/Dyslipoproteinemias
?Hypercholesterolemia
--- Content provided by FirstRanker.com ---
?Other Cardiovascular risk factorsUnchangeable Risk factors of Atherosclerosis
? Age
--- Content provided by FirstRanker.com ---
? Genetic Alterations? Male gender
? Men are at grater risk than are premenopausal
--- Content provided by FirstRanker.com ---
women, because of the protective effects of natural
Estrogens.
--- Content provided by FirstRanker.com ---
? Family history of premature coronary heart disease? Several genetically determined alterations in
lipoprotein and cholesterol metabolism have been
--- Content provided by FirstRanker.com ---
identified.
Changeable Risk Factors Of
--- Content provided by FirstRanker.com ---
AtherosclerosisvHyperlipidemias:
vThe presence of Hyperlipidemia is
--- Content provided by FirstRanker.com ---
the strongest risk factor for
atherosclerosis in persons younger
--- Content provided by FirstRanker.com ---
than 45 years of age.vBoth primary and secondary
--- Content provided by FirstRanker.com ---
hyperlipidemia increase the risk.Dietary Habits
? Eating a Balanced Diet
? Excess of Refined Sugars
--- Content provided by FirstRanker.com ---
? Excess of Saturated fatty acids? Use of Trans Fatty acids
Dyslipidemias
--- Content provided by FirstRanker.com ---
? Elevated LDL and Triacylglycerol ?directly associated with increase
risk
--- Content provided by FirstRanker.com ---
? Increased Serum HDL levels
? Increased LDL and decreased HDL
v Smoking: dose related
--- Content provided by FirstRanker.com ---
vDiabetes mel itusvMetabolic Syndrome
vIncreasing age and
--- Content provided by FirstRanker.com ---
male sex
vPhysical inactivity
vStressful life style
--- Content provided by FirstRanker.com ---
vHomocysteine is toxicto endothelial cel s
vC-Reactive Protein
--- Content provided by FirstRanker.com ---
?A Stressful life style:? Hormonal
Imbalances
--- Content provided by FirstRanker.com ---
?Oxidative Stress? Improvement of diet and
drugs may regulate the
--- Content provided by FirstRanker.com ---
levels of blood Lipoproteins
and Lipids which may
--- Content provided by FirstRanker.com ---
reduce the risk ofAtherosclerosis and CVDs.
vHypertension
--- Content provided by FirstRanker.com ---
vHigh blood pressure producesmechanical stress on the vessel
endothelium.
--- Content provided by FirstRanker.com ---
vIt is a major risk factor for
atherosclerosis in al age groups and
--- Content provided by FirstRanker.com ---
may be as important or moreimportant than hypercholesterolemia
after the age of 45 years.
--- Content provided by FirstRanker.com ---
vBlood Pressure >160 mmHg
increase the risk for MI
--- Content provided by FirstRanker.com ---
?Regulation of Hypertensionmay reduce the risk of
Atherosclerosis.
--- Content provided by FirstRanker.com ---
Less Well Established Risk Factors? There are a number of other less wel -established risk factors for
atherosclerosis, including:
--- Content provided by FirstRanker.com ---
? High Serum Homocysteine Levels
? Homocysteine is derived from the metabolism of dietary
--- Content provided by FirstRanker.com ---
Methionine? Homocysteine inhibits elements of the anticoagulant cascade
and is associated with endothelial damage.
--- Content provided by FirstRanker.com ---
? Elevated serum C-Reactive Protein
? It may increase the likelihood of thrombus formation;
--- Content provided by FirstRanker.com ---
? Inflammation marker? Infectious agents
? The presence of some organisms (Chlamydia pneumoniae,
--- Content provided by FirstRanker.com ---
herpesvirus hominis, cytomegalovirus) in atheromatous lesions
has been demonstrated by immunocytochemistry,
--- Content provided by FirstRanker.com ---
? The organisms may play a role in atherosclerotic developmentby initiating and enhancing the inflammatory response.
Reduction Of Atherosclerosis Risk
--- Content provided by FirstRanker.com ---
The risk of atherosclerotic event can
be decreased by:
--- Content provided by FirstRanker.com ---
?Normal Carbohydrate diet?Regular Exercise
?Smoking cessation
--- Content provided by FirstRanker.com ---
?Control of high pressure
?Drugs Statins, Ezetimibe,
--- Content provided by FirstRanker.com ---
?Intake of AntioxidantsCommon Arteries Atherosclerozied
?Aorta and its branches
?The Coronary arteries
--- Content provided by FirstRanker.com ---
? Large vessels thatsupply the Brain
3 Stages of Atherosclerosis:
--- Content provided by FirstRanker.com ---
1.Initiation and Formation Stage
2.Adaptation Stage
3.Clinical Stage
Pathogenesis Of Atherosclerosis
--- Content provided by FirstRanker.com ---
?Pathogenesis of
Atherosclerosis includes:
--- Content provided by FirstRanker.com ---
? Genetic Factors? Environmental Factors
The Development of Atherosclerosis
--- Content provided by FirstRanker.com ---
? The key event is ? damage to theendothelium.
? The damaged Endothelium
--- Content provided by FirstRanker.com ---
becomes more permeable to
Lipoproteins.
--- Content provided by FirstRanker.com ---
? Lipoproteins move below theendothelial layer (to intima).
? Damaged Endothelium loses its cel -
--- Content provided by FirstRanker.com ---
repel ent quality.?Inflammatory cel s move into the
vascular wal .
--- Content provided by FirstRanker.com ---
?Further Endothelial injury occurs by
attachment of leukocyte
--- Content provided by FirstRanker.com ---
(lymphocyte and monocyte) andPlatelet adherence
?Smooth muscle cel emigration and
--- Content provided by FirstRanker.com ---
proliferation
?Activated
--- Content provided by FirstRanker.com ---
macrophagesreleases free radicals
that oxidizes LDL.
--- Content provided by FirstRanker.com ---
vLipid Engulfment byMacrophages
vOxidized LDL engulfed by
--- Content provided by FirstRanker.com ---
Macrophages to form Foam cel s
vSubsequent development of an
--- Content provided by FirstRanker.com ---
atherosclerotic plaque with lipidcore
Effects Of Oxidized LDL
--- Content provided by FirstRanker.com ---
? Oxidized LDL is Toxic to the Endothelium:? Causing Endothelial loss
? Exposure of the subendothelial tissue to blood
--- Content provided by FirstRanker.com ---
components
? Chemotactic effect on lymphocytes and Monocytes
--- Content provided by FirstRanker.com ---
? Chemotactic effect on smooth muscle cells from thearterial media
? Stimulates production of MG-CSF, Cytokines,
--- Content provided by FirstRanker.com ---
adhesion molecules in the endothelium;
? Inhibits endothelium derived releasing factor
--- Content provided by FirstRanker.com ---
(EDRF), favoring vasospasm;? Stimulates specific immune system (production of
antibodies against oxidized LDL).
--- Content provided by FirstRanker.com ---
? Activated Macrophages also ingest
oxidized LDL to become foam cells,
--- Content provided by FirstRanker.com ---
? Which are present in all stages of
atherosclerotic plaque formation.
--- Content provided by FirstRanker.com ---
? Lipids released from necrotic foam
cells accumulate to form the lipid
--- Content provided by FirstRanker.com ---
core of unstable plaques/Fattystreaks.
?Endothelial disruption
--- Content provided by FirstRanker.com ---
leads :?Platelet adhesion and
aggregation
--- Content provided by FirstRanker.com ---
?Fibrin deposition
? Platelets and activated
--- Content provided by FirstRanker.com ---
macrophages release variousfactors that are thought to
promote growth factors
--- Content provided by FirstRanker.com ---
? This modulate the proliferation
of smooth muscle cells and
--- Content provided by FirstRanker.com ---
deposition of extracel ularmatrix in the lesions: Elastin,
Col agen, Proteoglycans.
--- Content provided by FirstRanker.com ---
? Thus Connective tissue synthesis
and Calcium fixation
--- Content provided by FirstRanker.com ---
determinates stiffness of blood
vessels.
--- Content provided by FirstRanker.com ---
? Which causes further ulcerationof Atheromatous plaque.
Arteriosclerosis
--- Content provided by FirstRanker.com ---
Summary Of Pathogenesis OfAtherosclerosis
? Accumulation of Lipids in vessel wal
--- Content provided by FirstRanker.com ---
? Source: Plasma Lipoproteins? Most important: Low-density lipoproteins LDL
? LDL transported inside macrophages to vessel
wal s
--- Content provided by FirstRanker.com ---
? Damage to Endothelium
? Adhesion of Macrophages
? Inflammation at the site
--- Content provided by FirstRanker.com ---
?Fatty Streaks?Foam cells
?Smal Thrombi
?Calcification
? Plaque formation
--- Content provided by FirstRanker.com ---
?Ulceration?Stiffening and Hardening
of blood vessels
Lesions Associated with
--- Content provided by FirstRanker.com ---
Atherosclerosis
? The lesions associated with
--- Content provided by FirstRanker.com ---
Atherosclerosis are of three types:?The Fatty streak
?The Fibrous Atheromatous plaque
?Complicated Lesion
--- Content provided by FirstRanker.com ---
? The latter two are responsible for
the clinical y significant
--- Content provided by FirstRanker.com ---
manifestations of the disease.? The more advanced complicated
lesions are characterized by:
--- Content provided by FirstRanker.com ---
?Hemorrhage?Ulceration
?Scar tissue deposits
? As a result of all pathogenic
--- Content provided by FirstRanker.com ---
mechanism
? Atherosclerosis can be defined
--- Content provided by FirstRanker.com ---
as vicious inflammatory process.Modern Theory of Atherosclerosis
? Multifactor Theory:
--- Content provided by FirstRanker.com ---
?Structural and functional injury of vascularendothelium
?The role of lipoproteins in initiation and
--- Content provided by FirstRanker.com ---
progression of lesions;
?Response to injury of immune cel s and
--- Content provided by FirstRanker.com ---
smooth muscle cel s?The role of growth factors and cytokines in
inflammation
--- Content provided by FirstRanker.com ---
?The role of repeated thrombosis in lesions
progression.
Consequences Of Atherosclerosis
--- Content provided by FirstRanker.com ---
OR
Effects/Complications
--- Content provided by FirstRanker.com ---
Of Atherosclerosis? Atherosclerosis is a chronic
process
--- Content provided by FirstRanker.com ---
? Atherosclerosis affects almost
al people with variable
--- Content provided by FirstRanker.com ---
severity.? Atherosclerosis develop over
several decades.
--- Content provided by FirstRanker.com ---
? If Congenital in origin It maystarts as early as infancy and
childhood,
--- Content provided by FirstRanker.com ---
? Progress very slowly during
life.
--- Content provided by FirstRanker.com ---
? Atherosclerosis contributesto more mortality and
--- Content provided by FirstRanker.com ---
? More serious morbidity thanany other disorder in the
western world.
--- Content provided by FirstRanker.com ---
? Atherosclerosis affects theintimal lining of endothelium
of
--- Content provided by FirstRanker.com ---
? Large and Medium-sized
elastic and muscular arteries
--- Content provided by FirstRanker.com ---
of body.?Atherosclerotic plaque
formation
--- Content provided by FirstRanker.com ---
?Narrows the diameter of
blood vessel lumen.
? Atherosclerosis leads to the
--- Content provided by FirstRanker.com ---
narrowing or complete blockage of
arteries /Occlusion by:
--- Content provided by FirstRanker.com ---
?Endothelial Dysfunction?Lipid deposition
?Inflammatory reaction in the vascular
--- Content provided by FirstRanker.com ---
wal
?Ulcerative Lesions
--- Content provided by FirstRanker.com ---
Atherosclerosis BringgsAlterations Of Arteries:
? Aneurysm-Excessive localized swelling of
--- Content provided by FirstRanker.com ---
blood vessel
? Stenosis-Abnormal narrowing of vessel
--- Content provided by FirstRanker.com ---
? Occlusion-Closing of blood vessel? Thrombosis-Local clotting of blood
? Embolism -blockage of vessel by lodging
--- Content provided by FirstRanker.com ---
of blood clot/fat globule
? Fissure-Small tear with bleeding
--- Content provided by FirstRanker.com ---
? Ulceration-Removal of top layer? Calcification- Accumulation of Calcium
Salts
--- Content provided by FirstRanker.com ---
? Atherosclerosis , can and does, occurin almost any artery in the body.
? Atherosclerosis of coronary arteries is
--- Content provided by FirstRanker.com ---
very crucial
? This blocks, the blood circulation to
--- Content provided by FirstRanker.com ---
Heart? Which fails the cardiac muscle to
sustain.
--- Content provided by FirstRanker.com ---
? Thus Atherosclerosis leads to
disease of cardiovascular
--- Content provided by FirstRanker.com ---
system affecting blood vesselwal .
? Causing Ischemic Heart Disease
--- Content provided by FirstRanker.com ---
which is the leading cause of
death in developed countries.
Biochemical Alterations
--- Content provided by FirstRanker.com ---
In Atherosclerosis
Biochemical Basis Of Atherosclerosis
--- Content provided by FirstRanker.com ---
? Low Blood supply to Cells/Tissues? Low Nutrient and Oxygen Supply to cells
? Low Metabolism in cells
? Low Oxidative Phosphorylation
? Low ATP production in cells
--- Content provided by FirstRanker.com ---
? Low Cellular Activity? Cellular/Tissue/Organ Dysfunction
? Irreversible Damage of cells/tissues/organ/system
Diagnosis Of Atherosclerosis
--- Content provided by FirstRanker.com ---
? Checking Lipid Profile/Lipoproteins? B.P
? ECG
? Angiography
? EEG
--- Content provided by FirstRanker.com ---
? Color Doppler? MRI
Management Of Atherosclerosis
? Reducing the risk factors
--- Content provided by FirstRanker.com ---
? Correcting the underlying causes? Angioplasty
? Other Surgeries
Complications of
--- Content provided by FirstRanker.com ---
Atherosclerosis
? 1. Acute Occlusion:
--- Content provided by FirstRanker.com ---
ThrombosisOcclusion
Ischemia, Infarction
--- Content provided by FirstRanker.com ---
? 2. Chronic Stenosis:
Chronic ischemia
--- Content provided by FirstRanker.com ---
AtrophyEg. Renal atrophy in renal artery stenosis, ischemic
atrophy of skin in DM
--- Content provided by FirstRanker.com ---
? 3. Aneurysm Formation:Extension to media
Aneurysm
Aneurysmal rupture eg. Abdominal
--- Content provided by FirstRanker.com ---
aortic aneurysm
? 4. Embolism:
--- Content provided by FirstRanker.com ---
Of atherosclerotic plaque or ofthrombi
? Thrombosis is the most
--- Content provided by FirstRanker.com ---
important complication of
Atherosclerosis.
--- Content provided by FirstRanker.com ---
? It is caused by slowing andturbulence of blood flow in the
region of the plaque and
--- Content provided by FirstRanker.com ---
ulceration of the plaque.
PHYSIOPATHOLOGICAL
CONSEQUENCES OF THE PLAQUE
--- Content provided by FirstRanker.com ---
v Coronary Artery Disease (CAD) : Angina, MI
v Cerebro Vascular Disease (CVD)
--- Content provided by FirstRanker.com ---
v Peripheral Artery Disease (PAD)
v Ischemic Stroke (Brain infarct)
--- Content provided by FirstRanker.com ---
v Secondary Erectile Disorder (ED)v Chronic Renal Ischemia ( Renal failure)
--- Content provided by FirstRanker.com ---
? Atherosclerosis commonly
leads to:
--- Content provided by FirstRanker.com ---
?Myocardial infarction?Stroke
?Gangrene of extremities
--- Content provided by FirstRanker.com ---
The Process of Atherogenesis
Progression of CHD
--- Content provided by FirstRanker.com ---
Damage to
endothelium and
--- Content provided by FirstRanker.com ---
invasion ofmacrophages
Smooth muscle
--- Content provided by FirstRanker.com ---
migration
Cholesterol
--- Content provided by FirstRanker.com ---
accumulatesaround
macrophage and
--- Content provided by FirstRanker.com ---
muscle cel s
Collagen and
--- Content provided by FirstRanker.com ---
elastic fibersform a matrix
around the
--- Content provided by FirstRanker.com ---
cholesterol,
macrophages
--- Content provided by FirstRanker.com ---
and muscle cel sPathogenesis of Coronary Heart Disease (CHD)
--- Content provided by FirstRanker.com ---
Plaque Build up in Artery
Overview of the Artery
--- Content provided by FirstRanker.com ---
The Development of Atherosclerosis
Monocyte Recruitment
--- Content provided by FirstRanker.com ---
LDLlumen
intima
--- Content provided by FirstRanker.com ---
Plaque Rupture and ThrombosisTissue Factor
Platelet Aggregation
--- Content provided by FirstRanker.com ---
Lipid Core
NO Inactivation Due to Oxidative Stress
--- Content provided by FirstRanker.com ---
Sch?chinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055Sch?chinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055
--- Content provided by FirstRanker.com ---
The Process of Atherogenesis ? an overviewFormation of Atherosclerotic Plaques
lumen
--- Content provided by FirstRanker.com ---
neointima
Lipid Core
--- Content provided by FirstRanker.com ---
Cardio Vascular Disorders (CVD)
--- Content provided by FirstRanker.com ---
Coronary Artery Disease (CAD)OR
Coronary Heart Disease(CHD)
--- Content provided by FirstRanker.com ---
OR
Ischemic Heart Disease(IHD)
--- Content provided by FirstRanker.com ---
Coronary Heart Disease? The term Coronary Heart Disease
(CHD) describes Heart disease
--- Content provided by FirstRanker.com ---
caused by impaired coronary
blood flow.
--- Content provided by FirstRanker.com ---
? In most cases, it is caused byAtherosclerosis of coronary
arteries which supply
--- Content provided by FirstRanker.com ---
Myocardium.
Clinical Manifestations
?The clinical manifestations
--- Content provided by FirstRanker.com ---
of Atherosclerosis depend
on:
--- Content provided by FirstRanker.com ---
?The vessels involved?The extent of vessel
obstruction
--- Content provided by FirstRanker.com ---
? Atherosclerotic Lesions produce theireffects through:
?Narrowing of the blood vessel and
--- Content provided by FirstRanker.com ---
production of Ischemia;
?Sudden vessel obstruction caused by
--- Content provided by FirstRanker.com ---
Plaque hemorrhage or rupture;?Thrombosis and formation of emboli
resulting from damage to the vessel
--- Content provided by FirstRanker.com ---
endothelium;
Coronary Artery Diseases Can cause:
--- Content provided by FirstRanker.com ---
?Angina/Chest Pain?Myocardial Infarction /Heart attack
?Cardiac dysrhythmias
--- Content provided by FirstRanker.com ---
?Conduction defects
?Heart failure
--- Content provided by FirstRanker.com ---
?Sudden deathMyocardial Infarction
Myocardial Infarction
--- Content provided by FirstRanker.com ---
? MI is an irreversible damageto Myocardium(Heart tissue)
? Acute myocardial infarction
--- Content provided by FirstRanker.com ---
(AMI), also known as a heart
attack
?AMI is caused due to
--- Content provided by FirstRanker.com ---
associated
Atherosclerotic disease
--- Content provided by FirstRanker.com ---
of the coronary arteries.Risk Factors OF MI
Uncontrollable
--- Content provided by FirstRanker.com ---
Control able
?Sex
--- Content provided by FirstRanker.com ---
?High blood pressure?High blood cholesterol
?Hereditary
--- Content provided by FirstRanker.com ---
?Smoking?Race
?Physical activity
--- Content provided by FirstRanker.com ---
?Obesity?Age
?Diabetes
--- Content provided by FirstRanker.com ---
?Stress and Anger--- Content provided by FirstRanker.com ---
--- Content provided by FirstRanker.com ---
Screening and Diagnosis
--- Content provided by FirstRanker.com ---
memea
a
--- Content provided by FirstRanker.com ---
s
s
--- Content provided by FirstRanker.com ---
ush
u
--- Content provided by FirstRanker.com ---
re
ows
--- Content provided by FirstRanker.com ---
rs
es
--- Content provided by FirstRanker.com ---
fic
eci
--- Content provided by FirstRanker.com ---
se
blood
--- Content provided by FirstRanker.com ---
sprical
Electro-
--- Content provided by FirstRanker.com ---
Stress
Coronary
--- Content provided by FirstRanker.com ---
ria
n
ect
--- Content provided by FirstRanker.com ---
cardiogram
Test
--- Content provided by FirstRanker.com ---
tS
Angiography
--- Content provided by FirstRanker.com ---
ro
el
--- Content provided by FirstRanker.com ---
io
te
--- Content provided by FirstRanker.com ---
c
s o
--- Content provided by FirstRanker.com ---
suf
p
--- Content provided by FirstRanker.com ---
to hear
ulses
--- Content provided by FirstRanker.com ---
plyimp
Narrowing in
--- Content provided by FirstRanker.com ---
Diagnosis Of MI
1. Pain
--- Content provided by FirstRanker.com ---
? Severe and Crushing,? Constricting, Suffocating.
? Usual y is Sub Sternal, radiating to the left
--- Content provided by FirstRanker.com ---
arm, neck, or jaw
? Gastrointestinal Complaints
--- Content provided by FirstRanker.com ---
?Sensation of Epigastric distress?Nausea and Vomiting
ECG
--- Content provided by FirstRanker.com ---
? Elevation of the ST segmentusually indicates acute myocardial
injury.
--- Content provided by FirstRanker.com ---
? When the ST segment is elevated
without associated Q waves, it is
--- Content provided by FirstRanker.com ---
called a Non?Q-wave Infarction.
Diagnostic Biochemical Markers Of MI
--- Content provided by FirstRanker.com ---
Enzymes and Proteins? Lipid Profile
? CK ?MB
--- Content provided by FirstRanker.com ---
? AST
? LDH 1 and LDH2
--- Content provided by FirstRanker.com ---
? Trop T and Trop I? Myoglobin
? Homocysteine
--- Content provided by FirstRanker.com ---
? hs CRP
? LP-PLA2
? Creatine kinase (CK), formerly called creatinine
--- Content provided by FirstRanker.com ---
phosphokinase, is an intracellular enzyme found
in muscle cells. Muscles, including cardiac
--- Content provided by FirstRanker.com ---
muscle, use ATP as their energy source.? Creatine Phosphate, which serves as a storage
form of energy in muscle, uses CK to convert
--- Content provided by FirstRanker.com ---
ADP to ATP.
? CK exceeds normal range within 4 to 8 hours of
--- Content provided by FirstRanker.com ---
myocardial injury and declines to normal within2 to 3 days.
? There are three isoenzymes of CK, with the MB
--- Content provided by FirstRanker.com ---
isoenzyme (CK-MB) being highly specific for
injury to myocardial tissue.
--- Content provided by FirstRanker.com ---
? Myoglobin is an Oxygen-Storing Protein, that isnormally present in cardiac and skeletal muscle.
? It is a small molecule that is released quickly from
--- Content provided by FirstRanker.com ---
infarcted myocardial tissue and becomes
elevated within 1 hour after myocardial cell
--- Content provided by FirstRanker.com ---
death, with peak levels reached within 4 to 8hours.
? It rapidly eliminates through urine (low
--- Content provided by FirstRanker.com ---
molecular weight).
? Because myoglobin is present in both cardiac and
--- Content provided by FirstRanker.com ---
skeletal muscle, it is not cardiac specific.? The Troponin complex consists of three
subunits
--- Content provided by FirstRanker.com ---
? Troponin C? Troponin I
? Troponin T
--- Content provided by FirstRanker.com ---
? These subunits are released during myocardial
infarction.
--- Content provided by FirstRanker.com ---
? Cardiac muscle forms of both troponin T andtroponin I are used in diagnosis of myocardial
infarction.
--- Content provided by FirstRanker.com ---
? Troponin I (and Troponin T) rises more
slowly than myoglobin
--- Content provided by FirstRanker.com ---
? This may be useful for diagnosis ofinfarction, even up to 3 to 4 days after the
event.
--- Content provided by FirstRanker.com ---
? It is thought that cardiac Troponin assays
are more capable of detecting episodes of
--- Content provided by FirstRanker.com ---
myocardial infarction in which cel damageis below that detected by CK-MB level.
Effects of Acute Myocardial
--- Content provided by FirstRanker.com ---
Infarction (AMI)? The principal biochemical
consequence of AMI is
--- Content provided by FirstRanker.com ---
? The conversion from aerobic to
anaerobic metabolism
--- Content provided by FirstRanker.com ---
? With inadequate production ofenergy(ATP) to sustain normal
Myocardial function.
--- Content provided by FirstRanker.com ---
? The ischemic area ceases to
function within a matter of
--- Content provided by FirstRanker.com ---
minutes, and? Irreversible Myocardial cell
damage occurs after 20 to 40
--- Content provided by FirstRanker.com ---
minutes of severe ischemia.
Treatment
? Reperfusion
--- Content provided by FirstRanker.com ---
? (Re-establishment of blood flow)
? Thrombolytic therapy
?Streptokinase/ Urokinase
--- Content provided by FirstRanker.com ---
? Revascularization procedures
?Early Reperfusion (within 15 to
--- Content provided by FirstRanker.com ---
20 minutes) after onset of
ischemia can prevent necrosis.
--- Content provided by FirstRanker.com ---
?Reperfusion after a longerinterval can salvage some of the
myocardial cells that would have
--- Content provided by FirstRanker.com ---
died because of longer periods of
ischemia.
--- Content provided by FirstRanker.com ---
Treatment 1) Stenting? A Stent (narrow expandable tube) is introduced into a blood vessel on
a bal oon catheter and advanced into the blocked area of the artery
--- Content provided by FirstRanker.com ---
? The bal oon is then inflated and causes the stent to expand until it fitsthe inner wal of the vessel, conforming to contours as needed
? The bal oon is then deflated and drawn back
?The stent stays in place permanently, holding the vessel open and
--- Content provided by FirstRanker.com ---
improving the flow of blood.
--- Content provided by FirstRanker.com ---
Treatment 2) Angioplasty
--- Content provided by FirstRanker.com ---
?Bal oon catheter is passed through the guiding catheter to the areanear the narrowing. A guide wire inside the balloon catheter is then
advanced through the artery until the tip is beyond the narrowing.
--- Content provided by FirstRanker.com ---
? The angioplasty catheter is moved over the guide wire until theballoon is within the narrowed segment.
? Balloon is inflated, compressing the plaque against the artery wall
? Once plaque has been compressed and the artery has been
--- Content provided by FirstRanker.com ---
sufficiently opened, the balloon catheter will be deflated and removed.
Treatment
--- Content provided by FirstRanker.com ---
3) Bypass surgery
? healthy blood vessel is removed from leg, arm or chest
? blood vessel is used to create new blood flow path in your heart
--- Content provided by FirstRanker.com ---
? the "bypass graft" enables blood to reach your heart by flowingaround (bypassing)
the blocked portion of
--- Content provided by FirstRanker.com ---
the diseased artery.
The increased blood
--- Content provided by FirstRanker.com ---
flow reduces anginaand the risk of heart
attack.
--- Content provided by FirstRanker.com ---
Peripheral Arterial Disease (PAD)
Peripheral Arterial Disease (PAD)
? PAD refers to the obstruction of
--- Content provided by FirstRanker.com ---
large arteries in lower extremities
of leg
--- Content provided by FirstRanker.com ---
? It possess, inflammatoryprocesses leading to stenosis, an
embolism, or thrombus formation.
--- Content provided by FirstRanker.com ---
Risk of PAD
? Risk of PAD also increases in
--- Content provided by FirstRanker.com ---
individuals who are:?Over the age of 50
?Male Obese
?With a family history of vascular
--- Content provided by FirstRanker.com ---
disease, heart attack, or stroke.
Symptoms OF PAD
? About 20% of patients with mild PAD may be
--- Content provided by FirstRanker.com ---
asymptomatic;
? Symptoms of PAD include:
--- Content provided by FirstRanker.com ---
? Pain, weakness, numbness, or cramping in musclesdue to decreased blood flow
? Sores, wounds, or ulcers that heal slowly or not at all
--- Content provided by FirstRanker.com ---
? Noticeable change in color (blueness or paleness) or
temperature (coolness) when compared to the other
--- Content provided by FirstRanker.com ---
limb? Diminished hair and nail growth on affected limb and
digits.
--- Content provided by FirstRanker.com ---
Prevention Of DyslipidemiasAnd Its
Consequences And Complications
--- Content provided by FirstRanker.com ---
?Get regular medical checkups
?Eat a Heart-Balanced healthy diet
?Control your blood pressure
?Check your Blood Cholesterol
--- Content provided by FirstRanker.com ---
?Don't smoke and drink Alcohol?Exercise regularly
?Maintain a healthy weight
?Manage stress
--- Content provided by FirstRanker.com ---
THE HEALTHY PLATE
--- Content provided by FirstRanker.com ---
FOODS THAT LOWER LDLCHOLESTEROL
1. Oats
--- Content provided by FirstRanker.com ---
2. Barley and Whole grains
3. Beans
--- Content provided by FirstRanker.com ---
4. Eggplant and okra5. Nuts
6. Vegetable oils (canola, sunflower, safflower)
--- Content provided by FirstRanker.com ---
7. Apples, grapes, strawberries, citrus fruits
8. Soy
--- Content provided by FirstRanker.com ---
9. Fatty Fish10. Fiber supplements
--- Content provided by FirstRanker.com ---
qEat meat sparinglyqAdd Fish to your diet
qGo for Nuts
--- Content provided by FirstRanker.com ---
qEat Fruits and Vegetables
qIncrease Complex Carbohydrates and fiber
--- Content provided by FirstRanker.com ---
qOpt for low-Fat dairy productsqCut down on Saturated fat in cooking
qAvoid Palm and Coconut oils ( Rich in SFAs)
--- Content provided by FirstRanker.com ---
qAvoid Trans Fats
qReduce Dietary Cholesterol
--- Content provided by FirstRanker.com ---
qReduce Salt intakeqWatch the Snacks
Blood Cholesterol levels increase
--- Content provided by FirstRanker.com ---
by eating these products
? Refined Sugars
? Beef
--- Content provided by FirstRanker.com ---
? Poultry? Fish
? Milk
? Eggs
? Cheese
--- Content provided by FirstRanker.com ---
? YogurtEXERCISE
--- Content provided by FirstRanker.com ---
qAerobic exercise (jogging, swimming, brisk walking,bicycling, etc)
STRESS REDUCTION STEPS
--- Content provided by FirstRanker.com ---
? Be Spiritual
? Balance All Actions
--- Content provided by FirstRanker.com ---
? Make and Fol ow Right protocols? Be Planned and Organized
? Manage works based on priority
--- Content provided by FirstRanker.com ---
? Involve In work which you are chosen for
? Be Obedient and Have Patience
--- Content provided by FirstRanker.com ---
? Be Happy with what get? Not expect too much in life
? Repent, Accept But Do Not Repeat
--- Content provided by FirstRanker.com ---
? Ventilate And Communicate
Summary To Prevent
--- Content provided by FirstRanker.com ---
? Eat right
? Watch your weight -even a modest drop in
--- Content provided by FirstRanker.com ---
weight can make a difference? Be Active - start a program of light exercise
for at least 30-45 minutes every day
--- Content provided by FirstRanker.com ---
? Lower your stress levels. Practice stress
reduction techniques
--- Content provided by FirstRanker.com ---
? Stop smoking and drinking alcohol? Be Spiritual
Avoid
--- Content provided by FirstRanker.com ---
Promote
Unhealthy eating
--- Content provided by FirstRanker.com ---
Healthy eating--- Content provided by FirstRanker.com ---
Visit your doctorRelaxation
regularly
--- Content provided by FirstRanker.com ---
Check your weight
Balance intake with output
--- Content provided by FirstRanker.com ---
Exercise regularlyInborn Errors Of Lipid Metabolism
Inborn Error Of Enzyme
--- Content provided by FirstRanker.com ---
AbnormalLipid
Deficient/
--- Content provided by FirstRanker.com ---
Accumulation
Metabolism
--- Content provided by FirstRanker.com ---
DefectOf
Sudden Infant
--- Content provided by FirstRanker.com ---
Acyl CoA
Acyl CoAs
--- Content provided by FirstRanker.com ---
Death SyndromeDehydrogenase
(SIDS)
--- Content provided by FirstRanker.com ---
Refsums Disease
-Phytanic Acid Phytanic Acid
--- Content provided by FirstRanker.com ---
OxidaseZellwegers
Peroxisomal
--- Content provided by FirstRanker.com ---
VLCFAs in
Syndrome
--- Content provided by FirstRanker.com ---
OxidationPeroxisomes
Inborn Error
--- Content provided by FirstRanker.com ---
Enzyme Defect
Abnormal
--- Content provided by FirstRanker.com ---
Lipid StorageAccumulation Of
Disorders
--- Content provided by FirstRanker.com ---
Niemann Picks
Sphingomyelinase Sphingomyelin in
--- Content provided by FirstRanker.com ---
DiseaseLiver and Spleen
Tay Sachs Disease Hexoseaminidase Gangliosides in
--- Content provided by FirstRanker.com ---
Defect
Tissues
--- Content provided by FirstRanker.com ---
Gaucher's Disease eta Glucosidase Glucosides in TissuesInborn Enzyme
Abnormal
--- Content provided by FirstRanker.com ---
ErrorDefect
Accumulation Of
--- Content provided by FirstRanker.com ---
Krabbe's Beta
Disease Galactosidase Galactocerebroside
--- Content provided by FirstRanker.com ---
Farbers CeramidaseCeramides
Disease
--- Content provided by FirstRanker.com ---
Role Of Insulin In Lipid Metabolism
? Insulin
--- Content provided by FirstRanker.com ---
? Stimulates LPL
? increased uptake of FA
--- Content provided by FirstRanker.com ---
from Chylomicrons andVLDL
? Stimulates Glycolysis
--- Content provided by FirstRanker.com ---
? increased glycerol
phosphate synthesis
--- Content provided by FirstRanker.com ---
? increases esterification? Induces HSL-phosphatase
? inactivates HSL
--- Content provided by FirstRanker.com ---
? Inhibits Lipolysis
? Net effect: TG storage
--- Content provided by FirstRanker.com ---
? Lack of Insulin?Free Fatty acids build up in
blood
--- Content provided by FirstRanker.com ---
?Can lead to excess Acetoacetic
acid production and buildup of
--- Content provided by FirstRanker.com ---
acetone (acidosis, which canlead to blindness and coma)
Insulin
--- Content provided by FirstRanker.com ---
Most Cel samino
Control
--- Content provided by FirstRanker.com ---
Protein synthesis
acids
--- Content provided by FirstRanker.com ---
MuscleGlucose uptake
Glycogen synthesis
--- Content provided by FirstRanker.com ---
Gastrointestinal
hormones
--- Content provided by FirstRanker.com ---
triglyceridesAdipose
Glucose uptake
--- Content provided by FirstRanker.com ---
Glycerol production
Triglyceride breakdown
--- Content provided by FirstRanker.com ---
AminoPancreas Insulin
Triglyceride synthesis
--- Content provided by FirstRanker.com ---
acids
Beta cells
--- Content provided by FirstRanker.com ---
LiverBlood
Glucose uptake
--- Content provided by FirstRanker.com ---
glucose
glucose
--- Content provided by FirstRanker.com ---
Glycogen synthesisFatty acid synthesis
Glucose synthesis
--- Content provided by FirstRanker.com ---
Brain
No effect
--- Content provided by FirstRanker.com ---
FeedbackGlucagon
Control
--- Content provided by FirstRanker.com ---
Adipose
Triglyceride breakdown
--- Content provided by FirstRanker.com ---
Fatty acids? Triglyceride storage
Exercise
--- Content provided by FirstRanker.com ---
Amino acids
Pancreas
--- Content provided by FirstRanker.com ---
Alpha cellsLiver
Glycogen breakdown
--- Content provided by FirstRanker.com ---
Glucose synthesis
Blood glucose
--- Content provided by FirstRanker.com ---
EpinephrineGlucose release
(stress)
--- Content provided by FirstRanker.com ---
Brain
No effect
--- Content provided by FirstRanker.com ---
Types Of Lipases
S.
Type Of Lipase
--- Content provided by FirstRanker.com ---
Location
No
--- Content provided by FirstRanker.com ---
Action Upon1
Lingual Lipase
--- Content provided by FirstRanker.com ---
Mouth
Dietary TAG
--- Content provided by FirstRanker.com ---
(Insignificant Action)2
Gastric Lipase
--- Content provided by FirstRanker.com ---
Stomach
Dietary TAG
--- Content provided by FirstRanker.com ---
(Insignificant Action)3
Pancreatic Lipase
--- Content provided by FirstRanker.com ---
Smal Intestine
Dietary TAG
--- Content provided by FirstRanker.com ---
(Significant Action)S. Type Of Lipase
Location
--- Content provided by FirstRanker.com ---
No
Action
--- Content provided by FirstRanker.com ---
4Lipoprotein Lipase
Endothelial Lining
--- Content provided by FirstRanker.com ---
Of Blood Vessels
Lipoprotein TAG
--- Content provided by FirstRanker.com ---
5Hormone Sensitive
Adiposecytes
--- Content provided by FirstRanker.com ---
Lipase
Hydrolyzes
--- Content provided by FirstRanker.com ---
Stored TAG6
Hepatic Lipase
--- Content provided by FirstRanker.com ---
Liver
TAG
--- Content provided by FirstRanker.com ---
7Phopshpholipase A2 Small Intestine
Phospholipids
--- Content provided by FirstRanker.com ---
QuestionsQ.1. Describe in details the digestion
& absorption of dietary form of lipids
--- Content provided by FirstRanker.com ---
& add a note on Steatorrhoea
OR
--- Content provided by FirstRanker.com ---
Q.1.What are different forms of
dietary lipids? How the dietary lipids
--- Content provided by FirstRanker.com ---
are digested & absorbed in G.I.T ?Q.2. What are the different modes of oxidation of
fatty acids in the body? Give -oxidation of even
--- Content provided by FirstRanker.com ---
chain fatty acid.OR
Q.2. Define -oxidation of fatty acid. Explain the
--- Content provided by FirstRanker.com ---
oxidation of Palmitate and calculate its
energetics./Fate of fatty acids in human body?
--- Content provided by FirstRanker.com ---
ORQ.2. Explain -oxidation of odd chain fatty acids.
Q.3. What is Lipogenesis? Describe in
--- Content provided by FirstRanker.com ---
details the De-novo synthesis of fatty
acid.
--- Content provided by FirstRanker.com ---
ORQ.3. Explain the Extra mitochondrial
synthesis of Palmitate.
--- Content provided by FirstRanker.com ---
Q.4. What is ketoacidosis? Give fate &formation ketone bodies.
? Short Notes
--- Content provided by FirstRanker.com ---
? Transport & storage of lipids / Rolelipoproteins.
? Emulsification & its significance / Role of
--- Content provided by FirstRanker.com ---
Bile salts in digestion & absorption of lipid.
? Lipolysis / Role of Hormone Sensitive
--- Content provided by FirstRanker.com ---
Lipase/Adipose tissue metabolism.? Clearing factor / Lipoprotein
lipase.
--- Content provided by FirstRanker.com ---
? Multi-enzyme complex of Fatty
acid biosynthesis / Fatty acid
--- Content provided by FirstRanker.com ---
synthesis complex.? Microsomal synthesis of fatty acid.
? Fatty liver /Lipotropic factors.
? Cholesterol-outline of Biosynthesis.
--- Content provided by FirstRanker.com ---
? Hypercholesterolemia ? causes &
consequences
--- Content provided by FirstRanker.com ---
? Atherosclerosis? Myocardial Infarction
? Enumerate the Inborn errors related to
--- Content provided by FirstRanker.com ---
lipid metabolism.
? Transport & Excretion of Cholesterol/
--- Content provided by FirstRanker.com ---
Reverse transport of cholesterol.? Fate & formation of Acetyl?CoA
? Fate of Propionyl-CoA
? Role of Carnitine in Lipid metabolism
--- Content provided by FirstRanker.com ---
? Role of Liver in Lipid metabolism.? TAG metabolism.
? Ketonemia & Ketonuria
? Represent the schematic structure of
--- Content provided by FirstRanker.com ---
lipoprotein.? Role of Citrate in lipid metabolism.
? Role of Carnitine in lipid metabolism.
? Hormonal Influence in Lipid
--- Content provided by FirstRanker.com ---
Metabolism
? Catabolism of Cholesterol.
? CETP activity
--- Content provided by FirstRanker.com ---
? HDL2 and HDL 3? Zellweger & Refsum's disease.
? Mixed Micelle
? Four types of Lipoproteins & their role
? Hyperlipoproteinemias
--- Content provided by FirstRanker.com ---
? Hypolipoproteinemia's? Different types of Lipases & their action.
Biochemistry Department