Download MBBS (Bachelor of Medicine, Bachelor of Surgery) 1st year (First Year) Biochemistry ppt lectures Topic 53 Lipid Metabolism Notes. - biochemistry notes pdf, biochemistry mbbs 1st year notes pdf, biochemistry mbbs notes pdf, biochemistry lecture notes, paramedical biochemistry notes, medical biochemistry pdf, biochemistry lecture notes 2022 ppt, biochemistry pdf.
LIPID METABOLISM
SYNOPSIS
1. DIETARY LIPIDS
?INGESTION
?DIGESTION
?ABSORPTION
?TRANSPORTATION
?UPTAKE BY TISSUES
2. LIPOLYSIS: LIPID CATABOLISM
q FATTY ACID OXIDATION
q KETONE BODY METABOLISM
3. LIPOGENESIS:
q LIPID BIOSYNTHESIS
q DE NOVO BIOSYNTHESIS OF FATTY ACIDS
4. LIPOPROTEIN METABOLIM/
TRANSPORTATION OF LIPIDS
5. DISORDERS ASSOCIATED TO LIPID
METABOLISM
INGESTION OF DIETARY LIPIDS/
EATING OF DIETARY LIPIDS
?Lipid is the chief
constituent of human
food.
Why To Eat Dietary Lipids?
OR
Importance Of Ingesting
Dietary Lipids
Importance Of Ingesting Dietary Lipids:
? To obtain TAG a secondary source of energy
for body tissues.
? To get source of Essential Fatty acids /PUFAs
structural components of tissues.
? To get source of Fat Soluble Vitamins
(Vitamin A,D,E and K) associated with Fatty
foods.
? To improve taste of recipes.
? To increase palatability and satiety value.
?Thus daily consumption of
dietary lipids is essential
?For the maintenance of
normal , growth, health and
reproduction of human
body.
In What
Amount & Form
The Dietary Lipids
to be Eaten?
? The daily consumption of dietary
Lipids by human beings varies and
depends upon:
?Dietary habits of an individual
?Economic status of a family
RDA OF DIETARY LIPIDS
?Per day quantity of dietary
Lipids for an adult
individual is:
?60-80 grams of dietary
Lipids in his/her diet.
FORMS AND SOURCES OF
DIETARY LIPIDS
Dietary Forms Of Lipids
? The dietary ingested Lipids contain fol owing
forms of Lipids:
?Triacylglycerol (TAG):Predominant
form of dietary Lipid - 98%.
?Phospholipids
?Cholesterol Ester
?Fat soluble Vitamins: are soluble in Fat
hence associated with fatty foods.
? The quality of ingested
Lipids should contain
adequate amounts of
Essential Fatty Acids
(PUFAs).
?The ideal ratio of dietary
Fatty acids in a TAG should
be :
PUFA : MUFA : SFA
1 : 1 : 1
Trans Fats are Detrimental To Health
? The sources of dietary Lipids
should be free from Trans Fatty
acids/less than 1%.
? Trans Fatty acids are not readily
metabolized by human body.
? Trans Fats increases the risk of
Atherosclerosis.
Dietary Rich Sources Of Lipids
?The dietary rich sources
of Lipids
?Obtained from foods of
Plant and Animal origin.
Sources Of Plant Lipids
q Plant Oils: Peanut ,Safflower
,Sunflower, Olive, Mustard Oils,
Margarine etc.
qNuts: Peanuts , Walnuts , Cashew
,Almonds, Sesame ,Pine etc
Sources Of Animal Lipids
?Milk
?Ghee, Butter , Cheese
?Egg Yolk
?Fish
?Animal-Fat ,Meat , Liver and Brain
Characteristics Of Food Fat Sources
Visible Fat
. Butter, Margarine, Salad oils and
dressing, Shortening Fat Meat
Invisible Fat
. Cheese, Cream portion of
homogenized milk, Egg yolk, Nuts,
Seeds, Olives.
Digestion Of Dietary Lipids In GIT
Digestion Of Dietary Lipids
Is
Cleavage Of Ester Bonds
Present In Various Lipid Forms
By
Lipases/Lipolytic Enzymes
In
Different Parts Of GIT
Insignificant Digestion
Of Dietary Lipids
Occurs in Mouth and Stomach
? Though the Salivary juice
contains Lingual Lipase and
Gastric juice contains Gastric
Lipase .
? The digestion of dietary Lipids in
mouth and stomach is negligible.
Insignificant Digestion Of Lipids In
Mouth and Stomach Due to:
?No optimal pH in juices for optimal
activity of Enzyme Lipases to act on
dietary Lipids of Mouth and Stomach
? No Emulsification Process in Mouth
and GIT
?As non polar Lipid droplets are
insoluble in the juices.
?Dietary Lipids do not have
contact with polar and soluble
Enzymes present in the
aqueous phase of salivary and
gastric juices.
?Since there is no contact of
dietary insoluble forms of Lipids
and soluble forms of Enzymes.
?There is no cleaving of the Ester
bonds of Lipid structures in the
salivary and gastric juices for
digestion of Lipids in mouth and
stomach.
Significant and Complete
Digestion
Of Dietary Lipids
Occurs In
Smal Intestine
After Emulsification
What Is Emulsification?
Emulsification is an Essential
Prerequisite Physicochemical
Process in Smal intestine
To
Initiate and Complete
Significant Digestion of
Dietary Lipids
?Emulsification is a
Physicochemical process
?Which forms Emulsions
from the dietary ingested
Lipids.
? Emulsification takes place in the
lumen of smal intestine.
? This is very essential process to
occur before the digestion of
dietary Lipids.
Requirements
Of
Emulsification
To Form Emulsions
? Emulsification takes place to form
Emulsions with the help of Emulsifying
agents:
?Emulsifying Agents/Surfactants:
? Bile Salts (Sodium Glycocholate, Sodium
Taurocholate)
? Amphipathic Lipids (present in diet)
?Mechanical force :
? Provided by peristaltic movement of
intestine.
? During the process of
Emulsification there is
dispersion of large droplets
of Fats/Oils
? Into smal , miscible droplets
which are termed as
Emulsions.
?Emulsions have non polar
lipids (TAG) in center
?Covered with a peripheral
layer of Bile salts and
Amphipathic Lipids.
Requirement Of Bile
In Smal Intestine
For Lipid Digestion and
Absorption
? Bile is a greenish fluid
produced in Liver.
? It is concentrated and is
stored in Gal bladder.
? Carried through bile duct
? Later secreted in Smal
intestine
?Cholecystokinin (CCK)
and Secretin
?Stimulates the:
Gal bladder to contract
and release bile.
Composition Of Bile
? Bile is an Alkaline solution
composed of:
?Bile Salts (Surfactant)
?Bilirubin (Bile Pigment)
?Cholesterol
?Lecithin
?Bile acids
Bile Acid
Role Of Bile Salts In Emulsification
?Name Of Bile salts :
?Sodium Glycocholate
?Sodium Taurocholate
?Bile salts present in the
bile have detergent like
action
?Bile salts are
emulsifying agents
?They are responsible for
fat Emulsification
? Bile salts present in Bile and
dietary Amphipathic Lipids by
their detergent like action:
?Reduces surface tension
?Increases surface area of
Fats/Oil and made them
miscible with aqueous phase.
? Emulsions bring non polar
dietary Lipids in close
contact with Lipid digesting
Enzymes present in aqueous
phase of intestinal juices.
Significance Of Emulsification
? Emulsification facilitate in the digestion of
dietary ingested Lipids in small intestine by:
?Reduces surface tension, increasing surface
area of Lipids
?Forms Emulsions
?Improves the miscibility of non polar Lipids
TAG in aqueous phase.
?Brings contact of dietary Lipids with Lipid
digesting enzymes.
?Facilitates cleavage of Ester bonds of
dietary Lipids.
Emulsions formed by Bile salts, Triacylglycerols and pancreatic lipase.
Action Of Specific
Lipid Digesting Enzymes
(Lipases)
in Smal Intestine
? Dietary forms of Lipids are
digested:
?By the action of specific Lipid
digesting enzymes
?Present in Pancreatic and
intestinal juice
?Digestion of Lipids is
cleavage of Ester
bonds present in their
structures.
Digestion Of Triacylglycerol
(TAG)
By Enzyme Pancreatic Lipase
? Dietary Fat/Oil which is chemically
TAG is the predominant ingested
Lipid form.
? TAG is predominantly and
significantly digested in smal
intestine
? After the process of Emulsification.
Action Of Pancreatic Lipase
? Digestion of Triacylglycerol is
cleaving of ester bonds present in its
structure.
? Triacylglycerol in small intestine is
specifically acted upon by enzyme
Pancreatic Lipase.
Colipase Facilitates
Pancreatic Lipase Activity
? Pancreatic Colipase
?Is activated by Trypsin
?Colipase interacts with
Triacylglycerol and Pancreatic Lipase
?Displaces Bile to allow recycling
?Improves activity of Pancreatic
Lipase
Role Of Pancreatic Colipase
? Secreted from Pancreas as
Procolipase
? Activated (cleaved) by
Trypsin
? Colipase anchors Lipase to
the Emulsion.
? One Colipase to one Lipase
(i.e., 1:1 ratio)
?Pancreatic Lipase digest
TAG
?By specifically cleaving first
and third ester bonds of
TAG structure.
? Pancreatic Lipase attack TAG at 1 and 3 positions of
Ester bonds.
G Fatty Acid1
G
l
l
y
Lipase
y
Fatty Acid1
c
c Fatty Acid
2 H
+
e Fatty Acid
2
2
20
e
r
r
Fatty Acid3
ol
ol
Fatty Acid3
Triacylglycerol
2-Monoacylglycerol
2 Free Fatty Acids
? The products of TAG digestion
? By Pancreatic Lipase activity
are:
?Free Fatty acids
?Monoacylglycerol (2MAG)
Bile Salts
Dietary Fat
Lipase 2-Monoacylglycerol
(large TG droplet)
+ 2 FFA
Lipid emulsion
Triacylglycerol
Colipase Pancreatic Lipase
Optimum PH 6 Cleaves 1st and 3 rd ester
bond of TAG
Free Fatty acids + 2-Monoacylglycerol
(Fatty acid esterified at C2 of Glycerol)
Action of Non Specific
Lipid Esterases
? Non specific Lipid Esterases act
on 2-MAG /Retinol Ester.
? It cleaves the ester bonds and
releases Free Fatty acid and
Glycerol/Retinol respectively.
2-Monoacylglycerol
Non Specific Esterase
Cleaves Ester bond at C2
Free Fatty acid + Glycerol
Digestion Of Phospholipids
by
Action of Phospholipase A2
and
Lysophospholipase
? The pancreatic juice enzymes
Phospholipase A2 and
Lysophospholipase digests
dietary Phospholipids.
Phospholipid
Phospholipase A2
Cleaves Ester bond at C2 of PL
Lysophospholipid+ Free Fatty acid
Lysophospholipid
Lysophospholipase
Cleaves Ester bond at C1
Glycerophosphorylcholine+ Free Fatty
acid
? Phospholipase A2 cleaves second
position ester bond of Phospholipid
and form Lysophospholipid and Free
Fatty acid.
? Lysophospholipid is then acted by
Lysophospholipase which cleaves ester
bond at C1 to generate:
Glycerophosphorylcholine and Free
Fatty acids.
Digestion Of Cholesterol Ester
By
Cholesterol Esterase
Cholesterol Ester
Cholesterol Esterase
Cleaves Ester bond at C3
Free Cholesterol+ Free Fatty acid
End Products Of Lipid Digestion
? 5 Simple Forms as End products of Lipid Digestion
1. Free Fatty acids
2. Glycerol
3. 2-Monoacylglycerol (2-MAG)
4. Glycerophosphoryl-Choline
5. Free Cholesterol
Absorption
of
Dietary End Products
Of Lipid Digestion
?Absorption of end
products of Lipid
digestion takes place in
smal intestine.
? The rate of absorption of
different types of Lipids differ.
?Pork fat is almost absorbed
completely.
?Castor oil is not at al absorbed.
Theories Of Lipid Absorption
? Absorption of Lipids is a complex
mechanism and various theories are
proposed to explain its mechanism.
?Lipolytic Theory
?Partition Theory
?Bergstorm Theory (Most Recent and
accepted one)
?The simple forms of
Lipids as digestive end
products are ready for
absorption.
Mechanism Of Lipid Absorption
? Bile Salts play an important role
in absorption of digestive end
products of dietary Lipids.
? Bile salts help in formation of
Mixed micel es.
?Mixed Micelle is a
aggregation of digestive
end products of dietary
Lipids with a peripheral
layer of Bile Salts.
?The efficiency of Lipid
absorption depends upon:
?The quantity of Bile salts
?Which solubilizes and
form Mixed Micelles.
Mixed Micel e Formation
? Mixed Micel e is a complex of Lipid
materials and Bile salts soluble in water
?It contains Bile salts, end products of
Phospholipids & Cholesterol at periphery
of a Mixed Micel es.
?2-Monoacylglycerol, Free fatty acids and
fat-soluble Vitamins in center of Mixed
Micel es.
Mixed Micel e Formation
? In the Mixed Micel e the non
polar long chain fatty acids
are at the center
? At the periphery are
Amphipathic Lipid moieties
and Bile salts.
? Bile salts and Amphipathic
Lipids of Mixed Micelle
? Exert a solubilizing effect on
non polar Lipid moieties and
help in their absorption.
? Mixed Micel es then get attached
to the intestinal mucosal cel
membrane.
? This help the Lipid end products to
slowly cross the mucosal
membrane.
? Bile salts of Mixed Micelles do
not cross the intestinal mucosal
cel membrane.
? They get retained in intestinal
lumen and later get recycled.
?The Bile salts are
reabsorbed further down
the Gastrointestinal tract
(in the ileum)
? Bile salts are transported
back to the Liver through
enterohepatic circulation
? Final y recycled and
secreted back into the
digestive tract
Re-Esterification of Simple Lipids
OR
Resynthesis Of Complex
Forms Of Lipids
In Intestinal Mucosal Cells
?Once the simpler forms of
Lipids enter the intestinal
mucosal cells
?They are resynthesized
into complex forms of
Lipids in the intestinal
mucosal cells.
? Free Fatty acid (FFA) + Glycerol Monoacylglycerol
? MAG +FFA Diacylglycerol
? Diacylglycerol + FFA
Triacylglycerol
? Glycerophosphorylcholine + FFAs
Phospholipid
? Cholesterol +FFA Cholesterol Ester
? Note the resynthesized
complex Lipids in intestinal
mucosal cel s
? Are usual y different from
those ingested through diet.
?The dietary absorbed
Lipids in intestinal
mucosal cells are then
mobilized out as
Lipoproteins.
Formation Of Lipoprotein
Chylomicrons
In Intestinal Mucosal Cells
For The
Transportation Of
Dietary Lipids
?The Lipids of dietary origin
present in intestinal
mucosal cells are mostly
non polar (TAG) and
hydrophobic in nature.
? The transport of these dietary
Lipids through aqueous phase of
lymph and blood is
? Facilitated through formation of
a Lipoprotein -Chylomicron in
intestinal mucosal cells.
? Lipoprotein Chylomicron is
formed in intestinal mucosal
cel s by
? Aggregation of dietary
ingested, digested and
absorbed Lipids and
Apoprotein (ApoB48).
? Chylomicron structure has the
non polar Lipids aggregated at
center, the Amphipathic Lipids
and Apoproteins are at
periphery.
?Chylomicron has 98% of
TAG (dietary origin)
?1% other Lipids and
?1% Proteins.
? Chylomicrons from intestinal
mucosal cells are first released in
Lacteals (Lymph vessels) of
Lymphatic system
? Which then enters the systemic
blood circulation via Thoracic
duct.
? Thus Chylomicron serve as a
vehicle for transporting the
exogenous forms of dietary Lipids
? From Smal intestine to Liver via
aqueous phase of Lymph and
Blood.
Lipid Digestion Absorption and
Transport
Mechanism Of
Lipid Absorption
Simple diffusion
Exocytosis
Short and
medium
chain fatty
acids
Overview
of Lipid
Digestion
and
Absorption
Absorption of Lipids
Absorption of fat.
Transportation Of
Chylomicrons
Through Blood Circulation
Action OF Enzyme Lipoprotein Lipase
On Lipoproteins
(Chylomicrons and VLDL)
Unlike
Plasma Lipid Clearance
OR
Role Of Clearing Factor
? Unlike Carbohydrates (Glucose) and
Protein (Amino acids) who use
enterohepatic circulation to reach first
to Liver.
? Most Lipids do use systemic circulatory
system.
? This allows Lipids to be cleared by the
whole body and avoids overwhelming
the Liver with Lipids.
? Most of the absorbed Lipids
from GIT mucosal cel s do not
directly enter the blood
stream.
? Instead, they are packaged
into Chylomicrons and first
released into the lymph.
? The lymph dumps into the Aortic arch (at
the Thoracic duct's connection with the left
Sub Clavian vein) .
? Where it then is transported through the
blood stream to be cleared and taken up
by:
?Adipocytes
?Liver
?Muscle
? Clearance of Lipoproteins
from circulation
? Is mediated by an enzyme
Lipoprotein Lipase (LPL)
acting upon TAG of
Lipoproteins.
? Nascent (New) Chylomicrons released
from intestinal mucosal cells are
circulated first through lymph and
then in systemic blood circulation.
? Nascent Chylomicrons in
blood circulation get matured
? After the receipt of Apo C I
and ApoE from HDL.
? Apo C I of Mature Chylomicron then
stimulates an enzyme Lipoprotein Lipase
(LPL)
? LPL associated in endothelial lining of
blood vessels, of Adipose, Heart,
and Skeletal Muscle tissue, as well as in
Lactating Mammary glands.
? Stimulated Lipoprotein Lipase then
acts upon the TAG of Lipoproteins
(Chylomicron and VLDL).
? Lipoprotein Lipase hydrolyze the TAG
of Lipoproteins to Free Fatty acids and
Glycerol.
? Released Glycerol and Free Fatty acids
enter the adjacent Adiposecytes.
? Glycerol and FFAs entered
in Adipocytes are
transformed into TAG.
? TAG is storage form of
Fatty acids
? TAG serve as a reserve
source of energy.
?The LPL by its activity
on Chylomicrons
reduces its content of
TAG.
? The Chylomicrons after the
action of LPL reaching to
Liver are
? Maximal y reduced with TAG
content and now termed as
Chylomicron Remnant.
? The Chylomicron remnant in
comparison to Nascent
Chylomicron is
? Smal er in size, and has very
less percentage of dietary
TAG, associated to it.
? Chylomicron remnants get fixed
to their specific receptors
present on Hepatocytes and get
internalized.
? The internalized Chylomicron
remnants inside the Liver gets
further metabolized.
? Lipoprotein Lipase is also
termed as Clearing Factor
? Since Lipoprotein Lipase clears
Lipaemic sera(Chylomicrons)
in post absorptive phase.
LPL Activity On Chylomicrons
? In Post absorptive phase most of the
blood Chylomicrons are transformed to
Chylomicron remnants
? By the Lipoprotein Lipase activity,
? The released moieties from Chylomicrons
are internalized by Adiposecytes and
Hepatocytes
? This clears the circulating Chylomicrons
from blood.
v Defect In Lipoprotein Lipase
Do not clear blood
Lipoproteins
Accumulates Chylomicrons
and VLDL in blood circulation
Heparin Is a Coenzyme For
Lipoprotein Lipase
? MI patients are administered
with Heparin injections
? Which may stimulate the
Lipoprotein Lipase activity
? And clear blood with elevated
Chylomicrons and VLDL.
Transport of Short Chain Fatty Acids
And
Medium Chain Fatty Acids
Is Different From
Long Chain Fatty Acids
? Transport of Short and Medium chain
Fatty acids
?These enter portal blood directly
from enterocytes
?Transported after bound to Albumin
in blood
?Albumin?FFA complex
?FFA which are internalized in Liver
?Oxidized to liberate ATPs
OR
?Elongated and used for TAG
formation
? Long-chain Fatty acids
?Transported in the form of
Chylomicrons
?Drain into the Lymphatics via the
Lacteal in Mammals
?Enter blood stream at the Thoracic
duct
Important Role Of Bile Salts In
Lipid Digestion and Absorption
? Bile Salts are formed in Liver
from Bile acids.
? Bile Salts are mixed and carried
through Bile via Common Bile
Duct(CBD) to small intestine.
? Bile Salts in intestine helps in
Emulsification of dietary Lipids to
form Emulsions and Facilitates Lipid
Digestion.
? Later Bile Salts form Mixed Micel es
and facilitates the absorption of
digestive end products Lipids.
Disorder Related
To Lipid
Digestion and Absorption/
Steatorrhoea
Steatorrhoea
? Steatorrhoea is a Malabsorption
condition
? Where there is no digestion and no
absorption of dietary Lipids in GIT
? Dietary ingested Lipids are excreted
out through feces
? Steatorrhoea leads to Fatty stools
Causes Of Steatorrhoea
? The basic cause to suffer from
Steatorrhoea is:
?Absence of emulsifying
agents- Bile salts in the smal
intestine.
?Absence of specific Enzymes
for Lipid digestion.
Thus Any Condition Affecting,
Synthesis, Secretion and
Transport of Bile to Intestine
leads to Steatorrhoea
? Extensive Liver damage
affects Bile Synthesis.
? Celiac Diseases: Sprue,
Crohn's Disease
? Surgical removal of intestine
? Obstructive Jaundice
? Obstruction due to
narrowing of bile duct after
surgeries
? Obstruction of CBD due to
Gal Stones
Biochemical Alterations in
Steatorrhoea
? No/Less Bile Salts in small
intestine
? No/Less Emulsification of
dietary Lipids
? No/Less Emulsions formed
? No/Less Contact of Lipids with
Lipases
? No/Less digestion of dietary Lipids
? No/Less formation of Mixed
Micelles
? No/Less absorption of dietary
Lipids
? More excretion of dietary Lipids
through feces.
Consequences Of Steatorrhoea
? In Steatorrhoea person suffers from
deficiency of essential Fatty acids
and Fat Soluble Vitamins.
? Body lacks exogenous TAG as
secondary source of Energy.
? Body lacks from Exogenous source of
Phospholipids and Cholesterol.
Diagnosis OF Steatorrhoea
? Determination Of Fecal Fat
? Microscopical y (Fat Globules present)
? Quantitatively (Gravimetric Method)
Chyluria
? Chylomicrons in Urine is termed as
Chyluria.
? Abnormal condition where
lymphatic drainage system opens
in urinary tract.
? Urine appears milky
? Chyluria occurs in Filariasis.
Chylothorax
? Chylomicrons in Pleural
fluid is termed as
Chylothorax.
? Abnormal y Thoracic duct
opens in pleural cavity.
Overview Of Lipid Metabolism
vLipid metabolism involves:
vLipolysis
vLipogenesis
vLiver and Adipose tissue play a
central role in Lipid metabolism.
vAdipose tissue is the main store
house of Triacylglycerol in the body.
vFatty acids are reduced
compound oxidized/catabolized
to Acetyl CoA
vFatty acids are biosynthesized
using Acetyl CoA as a precursor.
Lipid Metabolism
What Is Lipolysis?
OR
Role Of Hormone Sensitive Lipase
(HSL)
?In a well fed condition
TAG is stored as reserve
source of energy in
Adiposecytes.
Fat Storage in White Adipose Tissue
? Lipolysis occurs in emergency
conditions
? Lipolysis is the break down of
Depot Fat-Triacylglycerol(TAG)
? Into Free Fatty acids and
Glycerol
? By enzyme activity of Hormone
sensitive Lipase
Triacylglycerol
In Adipocytes Hormone Sensitive Lipase
Cleaves Ester bonds
Glycerol+ Free Fatty acid
?During Lipolysis the
secondary source of
energy TAG
?Stored as depot Fat gets
utilized.
Diagrammatic View Of Lipolysis
Conditions Of Lipolysis
? Lipolysis significantly and efficiently occurs :
?In emergency fasting condition
?In between long hours after meals
?When the primary source of energy
Glucose go below normal range in blood
?In presence of Hormones Glucagon or
Epinephrine
?By activity of Hormone Sensitive Lipase
? The Enzyme Hormone Sensitive
Lipase of Adipocytes is stimulated
By Hormones:
? Glucagon and Epinephrine
mediated via cAMP.
?On Lipolysis the Free Fatty
acids and Glycerol are
mobilized out of
adipocytes in blood
circulation.
End Products Of Lipolysis
?Free Fatty Acids
?Glycerol
Fate Of Glycerol After Lipolysis
? Glycerol (polar moiety)released in
emergency condition during
Lipolysis
? Is carried through blood and
enters in Liver and Muscles.
Fate Of Glycerol In Muscles
Glycerol Enter into
Glycolytic Pathway
(In Muscles)
Glycerol
Glycerol Kinase
Glycerol-3-Phosphate
Glyceraldehyde-3-PO4
?Glycerol of Lipolysis is
metabolized via Glycolysis
in Muscles
? Glycerol in muscles is
Phosphorylated to Glycerol-3-PO4
? Glycerol-3-PO4 is further oxidized
to Glyceraldehyde-3-PO4
? Thus Glyceraldehyde-3-PO4 in
Muscles make its entry in
Glycolysis
? Further gets metabolized to
generate energy (ATP) for
muscle activity.
Fate Of Glycerol In Liver
Glycerol Of Lipolysis
Is a Precursor For Gluconeogenesis
(In Liver)
Glycerol Is Used For Glucose
Biosynthesis In Liver
? Glycerol of Lipolysis is metabolized
via Gluconeogenesis in Liver
? Glycerol in Liver is Phosphorylated
to Glycerol-3-PO4 by Glycerol
Kinase
? Glycerol-3-PO4 is further oxidized to
? Glyceraldehyde-3-PO4 and isomerized
to DHAP
? This then is converted to Glucose.
? Thus Glyceraldehyde-3-PO4
in Liver make its entry in
Gluconeogenesis and
? Further gets metabolized to
produce Glucose.
?Glucose formed in Liver is
mobilized out into blood
and
?Supplied to Brain and
Hepatocytes in fasting
condition.
Fate Of Free Fatty Acids
After Lipolysis
? Non polar Long Chain Free Fatty
acids released in blood
circulation after Lipolysis are not
transported on its own.
? Needs the help of a polar moiety.
Polar Moiety Albumin
Transports
Long Chain Free Fatty Acids
In Blood
Released After Lipolysis
? Long chain Free Fatty acids are
uncharged/nonpolar/hydrophobic
? They are linked with polar Protein
moiety Albumin
? FFA-Albumin complex get
transported through blood
circulation.
? Albumin remain in the blood
circulation
? Free Fatty acids make its
entry in Muscle cel s.
Fatty Acids In Muscles
Oxidized To Liberate Energy
(ATP)
? Free Fatty acids are highly reduced
compounds.
? Free Fatty acids entered in Muscles
during emergency condition
? After Lipolysis, are oxidized to
liberate chemical form of energy
ATP.
?Thus after Glucose Free
Fatty acid serve as
secondary source of
energy to body tissues.
208
Oxidation Of Fatty Acids
OR
Catabolism/Degradation
Of Fatty Acids
How Fatty Acid Oxidation
Serve As
Energy Source?
? Fatty acids are an important
secondary source of energy to
body.
?Since Fatty acids are reduced
compounds
?Possess CH2-CH2 hydrocarbon bonds
with bond energy in their structures
? Oxidation of Fatty acid /Catabolism or
breakdown of Fatty acid is by:
?Removal of Hydrogen from hydrocarbon
chain (CH2-CH2).
?Which are temporarily accepted by
Coenzymes
?With formation of reduced Coenzymes
?Reoxidation of these reduced Coenzymes
by entry in ETC /Oxidative Phosphorylation
generates ATP.
?Oxidation of the Hydrocarbon
bonds of fatty acid chain makes
them weaker
?Easy Cleavage of hydrocarbon
bonds of Fatty acid
?Which helps in shortening of
the long Fatty acid chain.
Types Of
Fatty Acid Oxidation
1. Oxidation Based On Type Of Carbon Atom
? Alpha() Oxidation(Phytanic acid ?Branched Chain FA)
? Beta () Oxidation (Most Predominant)
? Omega() Oxidation (When defect in Oxidation)
2.Oxidation Based On Number Of Carbon
Atom
? Beta Oxidation of Even Carbon
Chain Fatty acid oxidation
? Beta Oxidation of Odd Chain
Fatty Acid Oxidation
? Very Log Chain Fatty Acid
(VLCFA) Oxidation
3.Oxidation Based On Nature Of
Bonds
? Oxidation of Saturated
Fatty acids
? Oxidation of Unsaturated
Fatty acids
4.Oxidation Based On Cel ular Site
? Mitochondrial Fatty acid
Oxidation
? Endoplasmic Reticulum Fatty
acid Oxidation
? Peroxisomal Fatty acid
Oxidation
The General
Pattern To Study
Metabolic Pathways
? Synonyms/Different Names of Pathway.
? What is the Pathway ? (In brief)
? Where the pathway occurs/Location?
(Organ/Cellular site)
? When pathway occurs/Condition?
(well fed/emergency/aerobic/anaerobic)
? What type Of Pathway?
(Catabolic/Anabolic)
? Requirements for the Pathway
(If Anabolic Pathway)
? How the pathway Occurs/Stages/Steps?
(Type of Rxn , Enzymes ,Coenzymes)
? Why the Pathway occurred?
(Significance of Pathway)
? Precursor, intermediates, byproducts and
end products of metabolic Pathway.
? Energetics of the pathway/Net ATP Use
and Generation
? Interrelation ships with other Pathways
? Regulation of Pathway :Modes of regulation.
? Regulatory Hormone/ Regulatory
Enzyme/Modulators.
? Inborn Error of the Metabolic Pathway
How Palmitic Acid is
Completely Oxidized In Human Body?
Calculate Its Energetics
Beta Oxidation
Of
Even Carbon
Saturated Fatty Acid
At Mitochondrial Matrix
Historical Aspects Of
Beta Oxidation of Fatty Acids
? Albert Lehninger showed that
? Oxidation of Fatty acids
occurred in the Mitochondria.
? Knoop showed that Fatty
acid is oxidized and
degraded by removal of 2-C
units
? F. Lynen and E. Reichart
showed that the 2-C unit
released is Acetyl-CoA, but
not free Acetate.
Beta Oxidation Of Palmitate (C16)
What Is Beta Oxidation
Of Fatty Acid ?
Definition Of Oxidation
of Fatty acid
? Oxidation of a Fatty acid at the
Beta Carbon atom/C3 (-CH2)
? Beta Oxidation of Fatty Acid is
the most predominant type of
Fatty acid oxidation.
? Most of the Fatty acids in the
cel s get oxidized and catabolized
via Beta Oxidation of Fatty Acid
b-Oxidation OF Fatty Acid
? b-oxidation of Fatty acids is the
catabolic/ degradative , energy
generating metabolic pathway of
Fatty acids
? It is referred to as the b-oxidation
pathway, because oxidation occurs at
the b-carbon (C3) of a Fatty acid.
? During Beta oxidation of
Fatty acid (-CH2) of Beta
position is oxidized and
? Transformed to Carbonyl
atom (-C=O)
? The oxidized and transformed Beta
positioned -C-H2 to -C=O during
the steps of Beta Oxidation Proper.
? Makes the bond between Alpha
and Beta Carbon Atom weaker
and cleavable to release 2Carbon
unit Acetyl-CoA.
The Weak bond between Alpha and Beta
Carbon Atom is Cleaved to release
2Carbon Unit Acetyl-CoA
? With a removal of 2-C units
there is shortening the Fatty
acid chain.
? The 2-C units released after
the steps of Beta Oxidation is
Acetyl-CoA (active Acetate)
which enters TCA for its
complete oxidation.
b-Oxidation OF Fatty Acid
Is a Catabolic Energy Producing
Pathway
Organs Involved with
Beta Oxidation Of Fatty Acid
?Skeletal Muscles
?Heart
?Hepatocytes
?Kidney
Cel ular Site For
Beta Oxidation Of Fatty Acid
?Cytosol
(Activation of Fatty acid)
?Mitochondrial Matrix
(Beta Oxidation Proper)
b-Oxidation pathway:
Fatty acids are degraded in the Mitochondrial Matrix via
the b-Oxidation Pathway.
Organs Which Do Not Operate
Beta Oxidation Of Fatty Acid
Remember In
Brain and Erythrocytes
Fatty Acids
Do Not Serve
As A Source Of Energy
?Free Fatty acids cannot
cross the blood brain
barrier
?Hence Fatty acids do
not enter Brain to get
oxidized.
? Beta Oxidation proper of Fatty
acid takes place in
Mitochondrial matrix
? Since mature RBC's has no
Mitochondria
? Hence no oxidation of Fatty
acids occurs in Erythrocytes.
? In emergency conditions
?Since Brain and Erythrocytes
cannot oxidize Fatty acids and
use as energy source.
?These organs has to depend
only on Glucose for getting
energy for their vitality.
Type Of Metabolic Pathway
? Beta Oxidation Of a Fatty acid is
a:
?Catabolic Pathway
?Degradative Pathway
?Energy generating metabolic
pathway in emergency phase
Condition Of Its Occurrence
? Usually Beta Oxidation of Fatty acids
efficiently occurs after Lipolysis.
? When there is low use of Glucose by body
cells
?In Fasting condition
?In between Meals
?During Severe Exercises and Marathon Races
?In Patients of Diabetes mellitus
Stages And Reaction Steps
Of Beta Oxidation Of Fatty Acids
Three Stages Of Beta Oxidation
For
Fatty acid Palmitate
Stage I
Activation of Fatty acid (Acyl Chain) to
Acyl-CoA In Cytosol
? Palmitate to Palmitoyl-CoA
In Cytosol
Stage II
Translocation of Activated Fatty acid
From Cytosol into Mitochondrial
Matrix
Through The Role of Carnitine
(Carnitine Shuttle)
Stage I I
Steps of Beta Oxidation Proper
In Mitochondrial Matrix
?Oxidation Reaction
?Hydration Reaction
?Oxidation Reaction
?Cleavage Reaction
Stage I
Activation Of Fatty acid
In Cytosol
Is a Preparative Phase
Site Of Fatty acid Activation
? Fatty acid(Acyl Chain) is activated
in Cytosol to Acyl-CoA .
? A long chain Fatty acid is termed as
Acyl chain.
? Every Fatty acid which undergoes
Oxidation of Fatty acid is first
activated to Acyl-CoA.
? Activation of a
Fatty acid means:
? Linking of Acyl Chain to
Coenzyme A to form Acyl-CoA
with a high energy bond.
? During Activation of
Fatty acid (Acyl Chain)
? `H' of CoA-SH (Coenzyme A) is
substituted by Acyl chain
? To form CoA-S Acyl, i.e Acyl-CoA an
activated Fatty acid.
?Thus CoA is a carrier of
Acyl chain in an
activated fatty acid.
Requirements of FA Activation
?Enzyme:
?Thiokinase /Acyl CoA Synthetase
?Coenzymes/Cofactor:
?CoA-SH
?ATP
?Magnesium ions (Mg++)
Steps Of Fatty Acid Activation
Activation of Fatty Acid
?An Acyl-CoA is an
activated energetic
compound having high
energy bond.
Activation Of a Fatty Acid
Is ATP Dependent
Converts ATP to AMP
Hence equivalent to 2 ATPs
? Thus formation of Acyl?CoA is
an expensive energetical y
CoezymeA (CoA-SH)
Activates
Fatty Acids
for Beta Oxidation
Acyl-CoA Synthetase/
Fatty Acid Thiokinase
condenses Fatty acids with CoA,
with simultaneous hydrolysis of
ATP to AMP and PPi
Fatty acid Activation
? Activation of Fatty acids is esterification
of Fatty acid with Coenzyme A
? In presence of Acyl-CoA Synthetase
(Thiokinase) forming an activated Fatty
acid as Acyl-CoA.
? This process is ATP-dependent, & occurs
in 2 steps.
? During the activation of Fatty acid
ATP is converted to AMP and ppi.
? Two high energy bonds of ATP are
cleaved and utilized in this activation
which is equivalent to 2 ATPs.
? Subsequent hydrolysis of PPi from
ATP drives the reaction strongly
forward.
? Note the Acyl- Adenylate is an
intermediate in the mechanism.
? There are different Acyl-CoA
Synthetase for fatty acids of
different chain lengths.
Activated Fatty Acid (Acyl-CoA)
is a High Energy Compound
Which Facilitates
The Second Stage
Of
Beta Oxidation Of Fatty Acid
Stage I
Translocation Of Acyl-CoA
From Cytosol
Into Mitochondrial Matrix
With The Help Of Carnitine
?-oxidation proper
occurs in the
Mitochondrial matrix.
? CoA part of Acyl-CoA is
impermeable to inner
membrane of Mitochondria
? Since CoA is a complex structure.
? Long-chain Fatty acids cannot be
directly translocated into the
Mitochondrial matrix.
? However short chain Fatty acids are
directly translocated into the
Mitochondrial matrix
? To translocate the activated long chain
Fatty acid (Acyl-CoA) from the cytosol to
the mitochondrial matrix
? Across the mitochondrial membrane
operates a specialized Carnitine Carrier
System.
What Is Carnitine?
? Carnitine is a functional, Non
Protein Nitrogenous (NPN)
substance.
? Carnitine is biosynthesized in the
body by amino acids Lysine and
Methionine.
?
? Long chain Acyl CoA traverses
the inner mitochondria
membrane with a special
transport mechanism called
Carnitine Shuttle.
Mechanism Of Carnitine
In Transport Of Fatty Acyl CoA
From Cytosol To Mitochondrial Matrix
? Acyl-CoA a high energy
compound cleave its high energy
bond in the second stage.
? The bond energy released is used
up for linking of Carnitine to Acyl
chain to form Acyl-Carnitine.
? Long-chain FA are converted to
Acyl Carnitine and are then
transported
? Acyl-CoA are reformed inside
the inner membrane of
mitochondrial matrix.
q Acyl groups from Acyl COA is
transferred to Carnitine to form Acyl
Carnitine catalyzed by Carnitine Acyl
Transferase I, in the outer mitochondrial
membrane
.
q Acylcarnitine is then shuttled across the
inner mitochondrial membrane by a
Translocase enzyme.
q The Acyl group is transferred back to CoA
of Mitochondrial pool in mitochondrial
matrix by Carnitine Acyl Transferase I .
q Finally, Carnitine is returned to the
cytosolic side by Protein Translocase, in
exchange for an incoming Acyl Carnitine.
Points To Remember
? Cell maintains two separate pools of
Coenzyme-A:
?Cytosolic pool of CoA
?Mitochondrial pool of CoA
?CoA is complex structure cannot
transport across Mitochondrial
membrane
?CoA linked to Fatty acid in
Mitochondria is different from
that CoA used for Fatty acid
activation.
Translocation of Palmitoyl-CoA
Across Mitochondrial
Membrane
ATP + CoA
AMP + PPi
palmitate
palmitoyl-CoA
Cytoplasm
OUTER
ACS
MITOCHONDRIAL
CPT-I
[1]
[2]
MEMBRANE
CoA
palmitoyl-CoA
Intermembrane
palmitoyl-carnitine
Space
carnitine
Activation of Palmitate to Palmitoyl CoA and conversion to Palmitoyl
Carnitine
CPT-I
palmitoyl-CoA
CoA
Intermembrane Space
Palmitoyl-Carnitine
Carnitine
INNER
CAT
[3]
MITOCHONDRIAL
MEMBRANE
Matrix
CPT-II
Carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Mitochondrial uptake via of Palmitoyl-Carnitine via the Carnitine-
Acylcarnitine Translocase (CAT)
ATP + CoA AMP + PPi
Cytoplasm
palmitate
palmitoyl-CoA
OUTER
MITOCHONDRIAL
ACS
CPT-I
MEMBRANE
[1]
[2]
CoA
Intermembrane
palmitoyl-CoA
Space
palmitoyl-carnitine
Carnitine
INNER
CAT
[3]
MITOCHONDRIAL
MEMBRANE
CPT-II
Matrix
carnitine
palmitoyl-carnitine
[4]
palmitoyl-CoA
CoA
Carnitine-mediated transfer of the fattyAcyl moiety into the
mitochondrial matrix is a 3-step process:
1. Carnitine Palmitoyl Transferase I, an enzyme on the
cytosolic surface of the outer mitochondrial membrane,
transfers a fatty acid from CoA to the OH on Carnitine.
2. An Translocase/Antiporter in the inner mitochondrial
membrane mediates exchange of Carnitine for Acylcarnitine.
3. Carnitine Palmitoyl Transferase I , an enzyme within the
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
matrix.
Stage I I
Steps of Beta Oxidation Proper/Cycle
In Mitochondrial Matrix
?Oxidation Reaction
?Hydration Reaction
?Oxidation Reaction
?Cleavage Reaction
Site/Occurrence Of
? Oxidation Proper
? In the Mitochondrial Matrix of
Cel s.
? After the reach of Acyl-CoA in
Mitochondrial matrix.
Mechanism Of Reactions
Of
Beta Oxidation Proper
of
Palmitoyl-CoA
Step I: Oxidation by FAD linked Acyl CoA
Dehydrogenase
Step I : Hydration by Enoyl CoA
Hydratase
Step I I: Oxidation by NAD linked
eta Hydroxy Acyl CoA Dehydrogenase
Step IV: Thiolytic Clevage Keto Thiolase
Palmitoylcarnitine
inner mitochondrial
Carnitine
membrane
respiratory chain
translocase
Palmitoylcarnitine
matrix side
1.5 ATP2.5 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
hydration
H2O
-Oxidation of
recycle
NAD+
Palmitoyl CoA
oxidation
6 times
NADH
cleavage
CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
Citric
O
acid
cycle
2 CO2
? Strategy of First 3 reactions of Beta
Oxidation proper is to
? Create a Carbonyl group (C=O) on
the -Carbon atom (CH2) of a Fatty
acid.
? This weakens the bond between
and Carbon atoms of Fatty acid.
? Fourth reaction cleaves the
"-Keto ester" in a reverse
Claisen condensation
reaction.
? Products of Each turn/cycle of
beta oxidation proper are :
?Acetyl-CoA
?Acyl-CoA with two carbons
shorter
Step 1
Role Of
Acyl-CoA Dehydrogenase
To Bring
Oxidation of the C-C bond
of Fatty acid
Acyl CoA Dehydrogenase is a
FAD linked Enzyme
(Flavoprotein)
? Acyl CoA Dehydrogenase catalyzes
Oxidation reaction
? Where there is a removal of
Hydrogen from alpha and beta
carbon atoms of Acyl-CoA.
? There forms a double bond
between C -C / C2 and C3 of
Fatty Acid.
? The product of this oxidation
reaction is - Unsaturated Acyl
CoA /Trans Enoyl CoA.
? Coenzyme FAD is the temporary
hydrogen acceptor in this oxidation
reaction .
? The reduced FADH2 is generated by
oxidation reaction of Acyl CoA
Dehydrogenase.
? FADH2 is then reoxidized, after its enter
into Electron Transport Chain
? Mechanism of Acyl CoA
Dehydrogenase involves :
?Proton Abstraction/Removes
Hydrogen
?Double bond formation
?Hydride removal by FAD
?Generation of reduced FADH2
? FADH2 is oxidized by entering into
ETC.
? Electrons from FADH2 are passed to
Electron transport chain
components,
? Coupled with phosphorylation to
generate 1.5 ATP
(By Oxidative Phosphorylation).
Acyl-CoA Dehydrogenase
? There are different Acyl-CoA
Dehydrogenases :
?Short Chain Fatty acids (4-6 C),
?Medium Chain Fatty Acids (6-10 C),
?Long (12-18 C) and very long (22 and
more)chain Fatty acids.
Inhibitor Of
Acyl CoA Dehydrogenase
?Acyl CoA Dehydrogenase is
inhibited by a Hypoglycin
(from Akee fruit)
Step 2
Role Of
Enoyl CoA Hydratase
To add water across the double bond
C = C of Trans-Enoyl-CoA
Saturate the double bond of Enoyl-CoA
Generate Hydroxyl group at beta carbon
?Enoyl-CoA Hydratase catalyzes
stereospecific hydration of the trans
double bond
?It adds water across the double bond
at C2 and C3 of Trans Enoyl CoA
?This hydration reaction generates
Hydroxyl (OH) group at beta
carbon atom of FA
?Converts Trans-Enoyl-CoA to
L -Hydroxyacyl-CoA
Step 3
Role Of
Hydroxyacyl-CoA Dehydrogenase
To Oxidizes the -Hydroxyl Group of
-Hydroxyacyl-CoA
And
Transform it into
-Ketoacyl-CoA
? -Hydroxyacyl-CoA Dehydrogenase is
NAD+ dependent
? It catalyzes specific oxidation of the
Hydroxyl group in the b position (C3) to
form a ketone group.
? NAD+ is the temporary electron acceptor
for this step which generates reduced
form NADH+H+
? The oxidation of
-Hydroxyacyl CoA produces a
product - Ketoacyl-CoA.
Step 4
Role Of b- Ketothiolase
/Thiolase
Catalyzes Thiolytic cleavage of the
two carbon fragment
by splitting the
bond between and carbons
? An enzyme -Keto Thiolase attacks
the -carbonyl group of -Ketoacyl-
CoA.
? This results in the cleavage of the
C-C bond.
? Releases Acetyl-CoA(2C) and an Acyl-
CoA (-2carbons shorter ).
Repetitions Of 4 Steps Of
Beta Oxidation Proper
? The b-oxidation proper pathway
is cyclic.
? 4 Steps of Beta Oxidation proper
are repeated
? Til whole chain of Fatty acid is
oxidized completely.
? The product, 2 carbons
shorter Acyl -CoA,
? Is the input to another
round/turn of the beta
oxidation proper pathway.
? Acyl CoA molecule released at end of
Beta Oxidation
? Is the substrate for the next round of
oxidation starting with Acyl CoA
Dehydrogenase.
? Repetition continues until all the carbon
atoms of the original Fatty acyl CoA are
converted to Acetyl CoA.
The shortened Acyl
CoA then undergoes
another cycle of beta
oxidation
The number of beta
oxidation cycles:
n/2-1, where n ? the
number of carbon atoms
Products Of Each Turn
Of
Beta Oxidation Proper
? Each turn/cycle of oxidation proper
generates one molecule each of:
?FADH2
?NADH+H+
?Acetyl CoA
?Fatty Acyl CoA ( with 2 carbons shorter each round)
Steps Of
-Oxidation Proper
of Fatty Acids Continues
With
A Repeated Sequence
of 4 Reactions
Til
A Long Fatty Acyl Chain Is
Completely Oxidized
?For an oxidation of Palmitic
acid through beta oxidation
? 7 turns/cycles of beta
oxidation proper steps occur.
Beta Oxidation
Fates of the products
of
-oxidation of Fatty Acid
? NADH+H+ and FADH2 - are
reoxidized in ETC to generate ATP
? Acetyl CoA - Enters the Citric acid
cycle(TCA cycle) for its complete
oxidation.
? Acyl CoA ? Undergoes the next
turn/cycle of oxidation proper.
Complete Oxidation Of Fatty Acids
Fatty Acid
Oxidation
Acetyl CoA +ATP
TCA Cycle
CO2 +H2O and ATP
? Fatty acid is activated and oxidized via
Beta Oxidation in specific number of
cycles depending upon chain length.
? Acetyl CoA an end product of Beta
oxidation of Fatty acid
? Is further completely oxidized via
TCA cycle.
1
Palmitoylcarnitine
inner mitochondrial
Carnitine
membrane
respiratory chain
translocase
Palmitoylcarnitine
matrix side
1.5 ATP2.5 ATP
Palmitoyl-CoA
FAD
oxidation
FADH2
Figure 4.
hydration
H2O
Processing and
NAD+
-oxidation of
recycle
oxidation
Palmitoyl CoA
6 times
NADH
cleavage
CoA
CH3-(CH)12-C-S-CoA + Acetyl CoA
Citric
O
acid
cycle
2 CO2
-Oxidation
Overal Flow
CAPILLARY
Lipoproteins
(Chylomicrons
L [2]
FABP
MITOCHONDRION
P
or VLDL)
FA
L
acetyl-CoA
TCA
A
[7]
[3]
cycle
[4] C
FA
FA
-oxidation
S
[6]
FA
FA
albumin
acyl-CoA
acyl-CoA
FABP
FABP
FA
[5]
carnitine
CYTOPLASM
transporter
[1]
from
fat
cel membrane
cel
FA = fatty acid
LPL = lipoprotein lipase
FABP = fatty acid binding protein
ACS = acyl CoA synthetase
Figure 2. Overview of fatty acid degradation
Energetics Of Beta oxidation
Of Palmitate
? Oxidation of Palmitic Acid C16
Number of turns of fatty acid
spiral = 8-1 = 7 Cycles of beta
oxidation proper.
? Generates 8 Acetyl CoA
During Electron Transport and
Oxidative Phosphorylation
Each FADH2 yield 1.5 ATP
and NADH 2.5 ATP
Energetics of Fatty Acid Beta Oxidation
e.g. Palmitic (16C):
1.-oxidation of Palmitic acid will be repeated in 7
cycles producing 8 molecules of Acetyl COA.
2.In each cycle 1 FADH2 and 1 NADH+H+ is produced
and will be transported to the respiratory chain/ETC.
? FADH2 1.5 ATP
? NADH + H+ 2.5 ATP
? Thus Each cycle of -oxidation 04 ATP
? So 7 cycles of -oxidation 4 x 7 = 28 ATP
1 Acetyl CoA yields 10
ATPs
via
TCA Cycle
? Review ATP Generation ?TCA/ Citric Acid
Cycle which start with Acetyl CoA
? Step
ATP produced
? Step 4 (NADH+H to ETC)
2.5 ATP
? Step 6 (NADH+H to E.T.C.) 2.5 ATP
? Step 10 (NADH+H to ETC) 2.5 ATP
? Step 8 (FADH2 to E.T.C.)
1.5 ATP
? 1 GTP
01 ATP
? NET per turn of TCA Cycle 10 ATP
1 ATP converted to AMP
during activation of
Palmitic acid to Palmitoyl-CoA
is equivalent to 2ATPs utilized
3. Each Acetyl COA which is oxidized
completely in citric cycle/TCA cycle gives 10
ATP
4. Hence 8 Acetyl CoA via TCA cycle (8 x 10 =
80 ATP)
5. 2 ATP are utilized in the activation of Fatty
acid
6. Energy gain = Energy produced - Energy
utilized
7. 28 ATP + 80 ATP - 2 ATP = 106 ATP
Thus On Complete Oxidation of
One molecule of Palmitate
106 molecules of ATP
are generated
ATP Generation from Palmitate Oxidation
Net yield of ATP per one oxidized Palmitate
Palmitate (C15H31COOH) - 7 cycles ? n/2-1
Palmitoyl CoA + 7 HS-CoA + 7 FAD+ + 7 NAD+ + 7 H2O
8 Acetyl CoA + 7FADH2 + 7 NADH + 7 H+
ATP generated
8 Acetyl CoA(TCA)
10x8=80
7 FADH2
7x1.5=10.5
7 NADH
7x2.5=17.5
108 ATP
ATP expended to activate Palmitate -2 ATP
Net yield of ATPs with Palmitate Oxidation: 106 ATP
Total End Products
Of
Beta Oxidation
Of
1 molecule of a Palmitic Acid
Palmitic acid
With 7 Turns of
Beta Oxidation Proper
Generates
8 Molecules Of Acetyl-CoA
7 FADH2+7 NADH+H+
-Oxidation Proper of Acyl-CoA
Summary of one round/turn/cycle of the
b-oxidation pathway:
Fatty Acyl-CoA + FAD + NAD+ + HS-CoA
+Acetyl-CoA
Fatty Acyl-CoA (2 C less) + FADH2 + NADH + H+
Stoichiometry for
Palmitic Acid Oxidation
b F
-O at
xi ty
da acyl
tion CoA
of
Saturated fatty acids
Regulation Of Beta Oxidation
Of Fatty Acids
?The Lipolysis and
Oxidation of Fatty acids
are well regulated by
Hormonal influence.
Insulin In Wel Fed Condition
? Insulin inhibits Lipolysis of Adipose
Fat (TAG) and mobilization of Free
Fatty acids.
? Insulin decreases Oxidation of
Fatty acids.
Glucagon In Emergency Condition
? When Cellular or Blood Glucose
lowers down there is secretion of
Glucagon.
? Glucagon and Epinephrine
stimulates Lipolysis in emergency
condition.
? Glucagon stimulates the Enzyme
Hormone sensitive Lipase and
hydrolyzes depot Fat(TAG).
? Glucagon mobilizes Free fatty
acids out into blood circulation
? Increases Oxidation of Fatty
acids.
Regulation Of
Beta Oxidation Of Fatty Acid
At Two Levels
? Carnitine Shuttle
? Beta Oxidation Proper
Transport of Fatty Acyl CoA
from
Cytosol
into Via Carnitine Shuttle
Mitochondrial Matrix
Is a Rate-limiting step
Malonyl-CoA
Regulates Beta Oxidation
At Carnitine Transport
Level
Malonyl-CoA Is an Inhibitor Of
Carnitine Acyl Transferase I
Malonyl-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)
inhibits Carnitine Palmitoyl Transferase I.
This Control of Fatty acid oxidation is exerted mainly at the
step of Fatty acid entry into mitochondria.
Acyl-CoA Dehydrogenase is
Regulatory or key Enzyme
of
Beta Oxidation Of Fatty Acids
Significance Of Beta oxidation
of a Fatty acid
?Beta oxidation cycles
helps in cleaving and
shortening of a long
chain Fatty acid
? Oxidation of Beta carbon
atom of a Fatty acid
transforms the stronger
bond between alpha and
beta carbon atom to a
weaker bond.
? Transformation to a weaker bond
helps in easy cleavage between
alpha and beta carbon
? During oxidation there is
dehydrogenation of beta carbon
atom (CH2 to C=O)
? The Hydrogen atoms removed during
beta oxidation are
? Temporarily accepted by the oxidized
coenzymes (FAD and NAD+) to form
reduced coenzymes
? Reduced coenzymes then final y enter
ETC and get reoxidized
? The byproduct of ETC is ATP
? Thus Beta oxidation of
Fatty acid
? Metabolizes a long chain
fatty acid with liberation of
chemical form of energy
ATP for cel ular activities.
Summary of -Oxidation
Repetition of the -Oxidation Cycle yields a succession of
Acetate units
? Palmitic acid yields eight Acetyl-CoAs
? Complete -oxidation of one Palmitic acid yields
106 molecules of ATP
? Large energy yield is consequence of the highly
reduced state of the carbon in fatty acids
? This makes fatty acid the fuel of choice for
migratory birds and many other animals
Disorders OF Beta Oxidation
Of Fatty Acids
Deficiencies of Carnitine
OR
Carnitine Transferase
OR
Translocase Activity
Are
Related to Disease State
Carnitine Shuttle Defects
?Affects the normal
function of Muscles,
Kidney, and Heart.
? Symptoms include Muscle
cramping, during exercise, severe
weakness and death.
? Muscle weakness occurs since
they are related with Fatty acid
oxidation for long term energy
source.
? Note people with the Carnitine
Transporter Defect
?Should be supplemented with a diet
with medium chain fatty acids
?Since the MCFAs do not require
Carnitine shuttle to enter
Mitochondria.
Sudden Infant Death Syndrome
(SIDS)
SIDS
? SIDS is a congenital rare disorder
with an incidence of 1 in 10,000
births.
? Cause: Due to the deficiency of
Enzyme Acyl-CoA Dehydrogenase a
regulatory enzyme of Oxidation
of Fatty acid.
? Consequences Of SIDS
? 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
? Leads to unexpected death of an infant.
Symptoms in defective Beta Oxidation of Fatty
acids include:
wHypoglycemia
wLow Ketone body production during
fasting
wFatty Liver
wHeart and/or Skeletal muscle defects
wComplications of pregnancy
wSudden infant death (SID).
? Hereditary deficiency of Medium
Chain Acyl-CoA Dehydrogenase
(MCAD),
? The most common genetic
disease relating to fatty acid
catabolism, has been linked to
SIDS.
Jamaican Vomiting Sickness
? Jamaican Vomiting Syndrome
is due to ingestion of unripe
Ackee fruit by people in
Jamaica
(Jamaica-Country of Caribbean)
Ackee Fruit
? The Ackee fruit is rich in
Hypoglycin ?A
? Hypoglycin is an inhibitor of
regulatory Enzyme Oxidation
Proper Acyl-CoA Dehydrogenase.
? The Jamaican Vomiting Disease leads
to complications characterized by :
?Severe Vomiting
?Hypoglycemia
?Convulsions
?Coma
?Death
Beta Oxidation
Of
Odd Chain Saturated Fatty Acids
-OXIDATION
OF
ODD-CHAIN FATTY ACIDS
?Odd chain carbon Fatty
acids are less common in
human body.
?Formed by some bacteria
in the stomachs of
ruminants and the human
colon.
? -oxidation of odd chain Fatty
acid occurs same as even
chain Fatty acid oxidation
? Until the final Thiolase
cleavage
? Which results in a 3 Carbon
Acyl-CoA /Propionyl-CoA
? Odd-carbon Fatty acids are
metabolized same as even carbon
chain Fatty acid via steps of
oxidation, releasing Acetyl CoA (2C)
in every turn.
? In the last turn of oxidation
proper of odd chain fatty acid
? Releases last three-C fragment as
Propionyl-CoA (3 C).
End Products Of Odd Chain Fatty Acid
Oxidation
? End products of b-oxidation of
an odd-number Fatty acid is :
?Acetyl-CoA(C2)
?Propionyl-CoA(C3)
Fate Of Acetyl-CoA
? Acetyl CoA released from beta
oxidation of odd chain fatty
acid
? Enter in TCA cycle and get
completely oxidized.
Fate Of Propionyl-CoA
Metabolism Of Propionyl CoA
Propionyl CoA
An End Product Of Odd Chain
Fatty Acid
Is Converted into
Succinyl CoA
A TCA intermediate
? Metabolism of Propionyl-CoA
? The Propionyl-CoA is
converted to Succinyl-CoA.
? Which is an intermediate of
TCA/Citric acid cycle
? Propionyl CoA metabolism is
dependent on Vitamin B
complex members:
?Biotin
?Vitamin B12
? Special set of 3 Enzymes are
required to further oxidize
Propionyl-CoA to Succinyl -CoA.
? Final Product Succinyl-CoA enters
TCA cycle and get metabolized.
? Three Enzymes convert Propionyl-
CoA to Succinyl-CoA:
1. Carboxylase
2. Racemase /Epimerase
3. Mutase
Step1
? Propionyl CoA is Carboxylated to yield
D Methylmalonyl CoA.
? Enzyme: Propionyl CoA Carboxylase
? Coenzyme: Cyto Biotin
? An ATP is required
Step2
? The D Methylmalonyl CoA
is racemized to the
L Methylmalonyl CoA.
? Enzyme: Methylmalonyl-CoA
Racemase/ Epimerase
Step 3
? L Methylmalonyl CoA is converted
into Succinyl CoA by an
intramolecular rearrangement
? Enzyme: Methylmalonyl CoA
Mutase
? Coenzyme of Vitamin B12 :Deoxy
Adenosyl Cobalamin
Fates Of Succinyl CoA
? Succinyl CoA
? Enters TCA cycle and get metabolized
? Serve as Glucogenic precursor for Glucose
biosynthesis in emergency condition
? Used as a precursor for Heme biosynthesis
? Involves in Thiophorase reaction of Ketolysis.
Oxidation of Odd-chain Fatty Acids
Conversion of Propionyl-CoA to Succinyl-CoA
Defects In Propionyl CoA Metabolism
? Deficiency of Enzyme Propionyl-CoA
Carboxylase will block the
metabolism of Propionyl-CoA.
? Accumulates Propionyl-CoA in blood
leading to Propionicacidemia.
? Deficiency of Vitamin B Complex
members affects Propionyl CoA
metabolism to Succinyl ?CoA.
? Vitamin B12 deficiency blocks the
Mutase reaction
? Accumulates L-Methyl Malonyl-
CoA leading to Methyl
Malonylaciduria.
Alpha Oxidation Of Fatty Acid
OR
Oxidation Of
Branched-Chain Fatty Acid
OR
Phytanic Acid Oxidation
? The source of Phytanic acid in
human body is through
ingestion of green leafy
vegetables.
? Phytanic acid is a breakdown
product of plant chlorophyl .
Why Phytanic Acid
Does Not Initiate With
Beta Oxidation Process?
? Phytanic acid is a Branched
chain FA.
? Has Methyl branches at odd
-number carbons.
? They are not good
substrates for -oxidation.
? The branched chain Phytanic
acid contains Methyl (CH3)
group at Carbon atom.
? Hence it cannot get oxidized
initial y via oxidation
pathway
?Thus initially Phytanic acid
fol ows Oxidation
?Modify Phytanic acid to
Pristanic acid and
?Further present it for
Beta Oxidation process.
Occurrence Of Alpha
Oxidation Of Phytanic Acid
Predominantly Alpha Oxidation
Of Phytanic Acid
Takes Place in
Endoplasmic Reticulum
of Brain Cel s
Also In Peroxisomes
Mechanism Of Alpha
Oxidation Of Phytanic Acid
? Phytanic acid 3,7,11,15-
Tetramethyl Hexadecanoic
acid
? Alpha oxidation removes the
Methyl groups at beta carbon.
? Later making the Fatty acid
ready for beta oxidation
process.
? During Oxidation there occurs:
? Hydroxylation at Carbon in
presence of Enzyme Hydroxylase or
Monoxygenase .
? This reaction is Vitamin C dependent
forming Hydroxy Acyl-CoA.
? Hydroxy Acyl-CoA is then
oxidized to Keto Acyl-CoA.
? The Ketonic group at Carbon
atom is decarboxylated
? Yielding CO2 molecule and a Fatty
acid with one Carbon atom less.
? Phytanic acid on alpha oxidation is
converted to Pristanic acid
? Which is further metabolized via
beta oxidation process to
generate Propionyl-CoA.
Products of Phytanic Acid Oxidation
? Alpha oxidation of Phytanic acid
Generates
?Acetyl-CoA
?Propionyl-CoA
?Isobutryl-CoA
Refsums Disease
Disorders Associated
With
Defective Oxidation
Of Phytanic Acid
?Refsums disease is a rare
but severe neurological
disorder.
?Caused due to defect in
Oxidation of Phytanic
acid
The Enzyme Defects
? Deficiency of Enzyme Phytanic
acid Oxidase/ Phytanol-CoA
Dioxygenase leads to Refsum's
disease.
? Biochemical Consequence Of Refsums
disease Is:
? No Oxidation of Phytanic acid
? Accumulation of Phytanic acid in
Brain cel s and Other Tissues
? Dysfunction of Brain
? Manifesting Neurological disorder
? Management Of Refsums
disease is :
? Avoid eating diet containing
Phytol /Phytanic acid.
Omega Oxidation Of Fatty Acids
?Omega Oxidation of Fatty
acid is:
?Oxidation of Omega Carbon
atom (CH3) of a Fatty acid.
When Does Omega Oxidation
Of Fatty Acid Occurs?
? Omega Oxidation takes
place when there is defect
in Oxidation of fatty acid.
?During Oxidation of
Fatty acid
? Carbon atom (CH3)
of a Fatty acid is
transformed to -COOH
? The omega oxidation forms
Dicarboxylic acid
? Which further undergo oxidation
? Form more short Dicarboxylic
acids Adipic acid and Succinic acid
? Which are more polar excreted
out in Urine.
-Oxidation of Fatty acids
Occur in the
Endoplasmic Reticulum
of Liver Cells
Mechanism Of Oxidation
? Oxidation of Fatty
acid is a minor
alternative oxidative
Pathway.
? Omega Oxidation of a Fatty
acid takes place with:
?Hydroxylation Reaction
?Oxidation Reaction
=Omega,the
lastletterinthe
Greekalphabet
? In Oxidation of Fatty acid there occurs
Hydroxylation at Carbon atom
? Converting into Primary terminal
Alcohol (-CH2OH) group.
? This reaction is catalyzed by NADPH+H+
dependent Cytochrome P450 system
? Next the primary terminal Alcohol group
is oxidized to form -COOH group .
? Further the Dicarboxylic acid
generated through Omega
Oxidation undergoes beta
oxidation
? To produce short chain
Dicarboxylic acids as Adipic acid
and Succinic acid
? Which are polar and excreted
out through Urine.
Significance Of Omega Oxidation
? Omega Oxidation transforms a
non polar Fatty acid to polar
Dicarboxylic fatty acid.
? Omega Oxidation of fatty acid
facilitates excretion of
accumulated fatty acids due to
defective normal Oxidation in
the cel s.
Peroxisomal Oxidation Of
Fatty Acids
OXIDATION OF FATTY ACIDS IN PEROXISOMES
? Peroxisomes ? Cell organelles
containing Enzymes Peroxidase and
Catalase
? These Enzymes catalyzes the
dismutation of Hydrogen peroxide
into water and molecular oxygen
When ? Why? How?
Does
Peroxisomal Oxidation
OF
Fatty Acid Occurs?
vb-Oxidation of very long-chain
fatty acids(>C22) occurs within
Peroxisomes initial y
v Later undergoes
Mitochondrial Oxidation .
? Carnitine is involved in transfer
of Very long Chain Fatty acids
(VLCFAS >C22) into and out of
Peroxisomes.
? Peroxisomal Fatty acid oxidation
is induced by a high Fat diet with
VLCFAs.
? To shortens the VLCFAs into
LCFAs
? Which are further degraded by
Beta oxidation process.
Peroxisomal -Oxidation
? Similar to Mitochondrial -
oxidation,
? Initial double bond formation
is catalyzed by Flavoprotein
Acyl-CoA Oxidase
Acyl CoA Oxidase?FAD transfers electrons to
O2 to yield H2O2.
? Coenzyme FAD is e- acceptor
for Peroxisomal Acyl-CoA
Oxidase, which catalyzes the
1st oxidative step of the
pathway.
? FADH2 generated at this step
instead of transferring the high-
energy electrons to ETC, as
occurs in Mitochondrial beta-
oxidation.
? Electrons of FADH2 directly go
to O2 at reaction level to
generate H2O2 in Peroxisomes.
? Thus FADH2 generated in
Peroxisomes by Fatty acid oxidation
do not enter ETC to liberate ATPs.
? Instead the peroxisome, FADH2
generated by fatty acid oxidation by
Acyl CoA Oxidase is reoxidized
producing Hydrogen peroxide.
FADH2 + O2 FAD + H2O2
The Peroxisomal enzyme Catalase
degrades H2O2:
2 H2O2 2 H2O + O2
These reactions produce No ATP.
? Once Very Long Chain Fatty acids
are reduced in length within the
Peroxisomes
? They may shift to the
Mitochondrial beta oxidation for
further catabolism of fatty acids.
?Fewer ATPs result
from Peroxisomal
oxidation of VLCFAs.
?Steps of Peroxisomal
Oxidation of Fatty acid
does not generate ATPs
?Instead the energy
dissipated in the form of
heat.
? Many drugs commercially available
in market for reducing obesity
? Stimulate Peroxisomal beta
oxidation
? Where the Fatty acids are oxidized
without much liberation of calories
(ATPs).
? Peroxisomal Oxidation of Fatty
acid efficiently takes place in:
?Obese persons
?Persons taking Hypolipidemic
drugs(Clofibrate).
Zel wegers Syndrome
OR
Cerebrohepatorenal Syndrome
Peroxisomal Disorder
? Zellweger
Syndrome
? Cerebro-Hepato-
Renal Syndrome
Biochemical Causes
?Rare genetic autosomal
recessive disorder.
?Characterized by
absence of functional
Peroxisomes.
?Gene mutations in
PEX Genes leads to
Zel wegers Syndrome.
Biochemical Alterations
? No oxidation of very long
chain Fatty acids and
branched chain fatty acids
in Peroxisomes
?Accumulation of large
abnormal amounts of VLCFAs
in Peroxisomes of tissues.
?No normal function of
Peroxisomes.
? Progressive degeneration of
Brain/Liver/Kidney, with
death ~6 month after onset.
Signs and Symptoms
? Defect in normal function of multiple organ
system.
? Impaired neuronal migration, positioning and
brain development.
? Hypomyelination affecting nerve impulse
transmission.
? Hepatomegaly
? Renal Cysts
? Typical Dysmorphic facies.
Diagnosis
?Detection of Increased
levels of Serum Very
Long Chain Fatty Acids-
VLCFAs
Oxidation Of Unsaturated
Fatty Acids
? PUFAs having double bonds in their
structure are unstable.
? The double bonds are hydrolyzed and
metabolized faster than saturated
bonds.
? Thus dietary intake of PUFA get
readily metabolized
? Which reduces risk of
Atherosclerosis.
Mechanism Of Oxidation
Of Unsaturated Fatty
Acids
? Initial and later the Oxidation
of PUFAs is by
? Similar steps of Oxidation
in the parts, of saturated
bonds.
? The double bonds of UFAs are cleaved
by the action of Fol owing Enzymes:
? Isomerase (Enoyl CoA Isomerase)
(For even numbered double bonds MUFAs)
?Reductase (2,4 Dienoyl CoA Reductase)
(For Odd numbered double bonds PUFAS)
?Epimerase
(Converts D Isomer to L Isomer)
? Enoyl CoA Isomerase handles
odd numbered double bonds
in MUFAs.
? 2,4 Dienoyl CoA Reductase
handles even numbered
double bonds in PUFAs.
? Usually natural unsaturated fatty
acids have cis double bonds.
? Which is transformed to trans
double bonds by the action of an
Isomerase .
? As the next enzyme to act is
Enoyl Hydratase ,which acts
only on trans double bonds.
? Enoyl-CoA Isomerase converts
Cis unsaturated Fatty acids to
Trans- 2 Enoyl-CoA
? Now the -oxidation can
continue on with the hydration
of the trans- 2-Enoyl-CoA by
Enoyl CoA Hydratase
Oxidation Of
Monounsaturated Fatty Acids
? Oleic acid, Palmitoleic acid
? Normal -oxidation for three cycles
? Cis-3 Acyl-CoA cannot be utilized by
Acyl-CoA dehydrogenase
? Enoyl-CoA Isomerase converts this to
trans- 2 Acyl CoA
? -oxidation continues from this point
Oxidation Of
Polyunsaturated Fatty Acids
Slightly more complicated
? Same as for Oleic acid, but only up to a point:
? 3 cycles of -oxidation
? Enoyl-CoA Isomerase
? 1 more round of -oxidation
? trans- 2, cis- 4 structure is a problem.
? 2,4-Dienoyl-CoA Reductase transform it to odd numbered.
Oxidation of Unsaturated Fatty Acids (Remember they are cis!)
b-oxidation of fatty acids with even
numbered double bonds
? The Oxidation of PUFAs provide less
energy than saturated Fatty acids as
they are less reduced compounds.
? At double bonds the Isomerase act
and convert it into Trans ?Enoyl
CoA.
? This bypasses the Acyl-CoA
Dehydrogenase ?FAD linked beta
oxidation reaction.
? 1.5 ATP less per double bond.
Ketone Body
Metabolism
Formation And Fates
Of
Ketone Bodies
In Human Body
Ketogenesis And Ketolysis
OR
Formation And Breakdown
Of Ketone Bodies
What are Ketone Bodies ?
When ? Where? Why?
and How?
Ketone Bodies are Formed
In The Human Body???
Incomplete Oxidation
Of Fatty Acids And There Products
? Ketone body Metabolism Includes:
?Ketogenesis : Formation of Ketone
bodies
?Ketolysis: Breakdown and Utilization
of Ketone bodies
?Ketosis: Imbalance in Ketogenesis and
Ketolysis.
Ketogenesis
What Is Ketogenesis?
? Ketogenesis is biosynthesis
of Ketone bodies
? In emergency conditions at
Mitochondrial matrix of
Hepatocytes.
Condition In Which Ketogenesis Occurs
? Ketogenesis efficiently occur in
Emergency conditions
?Fasting/Starvation Phase
?Low Cel ular Glucose Metabolism
Site For Ketogenesis
OR
Where Does Ketogenesis
Occurs ?
? Ketone bodies are biosynthesized
in the Liver/Hepatocytes at the
Mitochondrial Matrix
? Formed Ketone bodies come out of
Mitochondria
? Later they are diffused into the
blood and are
? Transported to reach extrahepatic
/peripheral tissues
Who Is The
Precursor For Ketogenesis ?
?Acetyl CoA is the
precursor/starting
material for
Ketogenesis.
Source Of Acetyl-CoA For Ketogenesis
? Ketone bodies are formed from
Acetyl CoA ,obtained through
increased beta oxidation of
Fatty acids.
? Acetyl-CoA accumulated in
Mitochondrial matrix due to
underutilization via TCA
cycle.
Biochemical Basis for
Ketogenesis
OR
What Favors Ketogenesis ?
OR
Why Ketogenesis Occurs In
Emergency Condition ?
What Factors
Promotes/Triggers
Ketogenesis ?
Biochemical Causes for Ketogenesis
? In Emergency Condition
?Due to Cel ular Glucose
deprivation and its metabolism
?Low Cel ular Oxaloacetate
?Low Operation of TCA cycle
? Normal Insulin activity do
not promote Ketogenesis.
? Low Insulin activity
promotes Ketogenesis.
Remember
? Availability of Glucose in cel s, do
not promote Ketogenesis and
form Ketone bodies.
? Unavailabity of Glucose in cel s
promote Ketogenesis and form
Ketone bodies
Way For KETOGENESIS
REVIEW!
?When the body cel s has
plenty of Carbohydrates
(Glucose) available as
primary energy source,
?Glucose is completely
oxidized to CO2,H2O and
ATPs.
?When the body has excess
Glucose available it is utilized
as below:
? Required amount of Glucose
is ful y oxidized
?Stored as Glycogen
?Transformed to fatty acids
and stored as TAG.
? When cell Glucose go below sub normal
? Fatty acids undergo -oxidation to form
Acetyl-CoA.
? Normally, Acetyl-CoA is further oxidized via
TCA cycle.
In Emergency
How Acetyl-CoA Gets Accumulated
And Diverted For Ketogenesis ?
? In Emergency Condition
? When Cel ular Glucose is low
? In response to hormones Glucagon and
Epinephrine
? There is increased Lipolysis and beta
oxidation Fatty acids.
? In emergency conditions
? Cellular Glucose levels decreases
? This decreases cel ular Oxalo acetate
(OAA).
?Since source of OAA is Glucose
(By Pyruvate Carboxylation Rxn).
?Also in emergency conditions OAA is
used for Gluconeogenesis which
lowers cel ular OAA.
? OAA is the starting material required to
initiate and operate TCA .
? Due to low levels of cel ular OAA, end
product of Fatty acid oxidation- Acetyl-
CoA is not utilized via TCA cycle.
? The underutilized Acetyl-CoA in the
Mitochondrial matrix of Liver gets
accumulated.
What Are
The Steps Of Ketogenesis?
Precursor For Ketogenesis
? Is Acetyl-CoA
? In Emergency condition
? Acetyl ?CoA obtained from increased beta
oxidation of Fatty acids in cel ular Glucose
deprived conditions
? Which accumulates Acetyl-CoA in
Mitochondrial matrix due to low/no
utilization of Acetyl-CoA via TCA cycle is
diverted for Ketogenesis.
Decarboxylation
q Acetoacetate produces -Hydroxybutyrate
in a reduction reaction catalyzed by -
Hydroxybutyrate Dehydrogenase in the
presence of NADH+H+
Isoprenesand
Steroids
Fatty acid
2 Acetyl CoA
oxidation to CO2
Citric
-oxidation
acid
(excess
cycle
Thiolase
acetyl CoA)
CoA
Acetoacetyl CoA
acetyl CoA
HMG-CoA synthase
CoA
MITOCHONDRIAL MATRIX
Hydroxymethylglutaryl CoA
HMG-CoA-lyase
acetyl CoA
Acetoacetate
NADH
(non-enzymatic)
-Hydroxybutyrate
dehydrogenase
Acetone
NAD+
-Hydroxybutyrate
Formation of
ketone bodies
HMG, 3-hydroxy-3-methylglutaryl
Both enzymes
must be present in
mitochondria for
Ketogenesis to take
place.
Pathways of ketogenesis in the liver
? Three molecules of Acetyl-
CoA are involved during
the steps of Ketogenesis.
? Ketone bodies can be simply
referred as
? Condensed and modified
forms of Acetyl-CoA
?Ketone Bodies are partial y
oxidized products of Fatty
Acids (Half broken products
of Fatty acids)
? Obtained through steps of
Ketogenesis.
?The end product of Beta oxidation
of Fatty acid - Acetyl-CoA, if not
completely oxidized and utilized via
TCA cycle
? The complex ,impermeable,
accumulated Acetyl-CoA is diverted
for Ketogenesis and transformed to
permeable Ketone bodies brought
out of Mitochondria and cel into
blood circulation.
Description Of Reaction Of
Ketogenesis
? Two molecules of Acetyl-CoA
formed as an end product of -
oxidation condenses with one
another to form Acetoacetyl ?
CoA
? This reaction is by a reversal of
the Thiolase reaction by an
enzyme Acetoacetyl-CoA Thiolase.
nAcetoacetyl-CoA, which is the
starting material for
Ketogenesis,
nMay also arises directly from
the terminal four carbons of a
fatty acid during -oxidation.
? The further steps of Ketogenesis
involves:
? Synthesis and breakdown of
Hydroxy Methyl Glutaryl-CoA/
3-Hydroxy-3-Methylglutaryl-CoA
(HMG CoA) from Acetoacetyl-CoA.
? By two key Enzymes:
? HMG-CoA Synthase
? HMG-CoA Lyase
?Subsequently in the
second step a third
molecule of Acetyl CoA
is added to Acetoacetyl
CoA.
nCondensation of Acetoacetyl-
CoA with another molecule of
Acetyl-CoA to form 3-Hydroxy-
3-Methylglutaryl CoA (HMG
CoA)
nCatalyzed by HMG-CoA
Synthase.
? These two steps are identical
to the first two steps in the
Cholesterol biosynthesis
pathway.
? In the third step 3-Hydroxy-3-
Methylglutaryl-CoA Lyase
(HMG-CoA Lyase) split off
HMG-CoA
? To release Acetyl-CoA and
Acetoacetate.
v Both Acetoacetate and -Hydroxybutyrate
are permeable through mitochondrial
membrane.
v Can be transported across the mitochondrial
membrane and the plasma membrane of
the Liver cells,
Ketone bodies enter to the blood stream to
be used as a fuel by extrahepatocytes/other
cells of the body.
6. In the blood stream, small
amounts of Acetoacetate are
spontaneously (non-
enzymatically) Decarboxylated
to Acetone.
7. Acetone is a secondary
,volatile, Ketone body expired
out by Lungs.
Acetone is soluble and volatile
and cannot be detected in the
blood and expired out by Lungs.
The odor of Acetone may be
detected in the breath
Also the urine of a person has high
level of ketone bodies in the blood
(Ketonuria)
Condition where more Acetone is
produced and expired out gives fruity
odor also termed as Acetone
Breath/Kussmauls Breathing.
Acetone Breath is noted in persons
with Prolonged Starvation and
Diabetic Ketoacidosis.
? Hydroxy Butyrate is an acidic
compound.
? High levels of Hydroxy Butyrate in
blood
? May lower blood pH and leads to a
condition of Metabolic Acidosis.
? Acidosis due to increased Ketone
bodies is termed as Ketoacidosis.
?Ketone bodies formed by
Liver are mobilized out
?Circulated in blood and
they may enter extra
hepatic tissues for its use.
What are Ketone Bodies?
Ketone bodies are
Ketone group containing compounds
Obtained from Acetyl-CoA
By Steps of Ketogenesis
Permeable, Soluble
Intermediate Products, of Incomplete
Oxidation of Fatty Acids
Produced in Emergency Conditions
At Mitochondrial Matrix Of Hepatocytes
Due to Cel ular Glucose Deprivation
Name Three Ketone Bodies
? The Three Ketone bodies present
in human body are:
?Acetoacetate
?Acetone
?b- Hydroxybutyrate
Structures Of
Ketone Bodies
Acetoacetate
Is the First Ketone body
To Be Formed
Hence Termed As
Primary Ketone Body
1)Primary Ketone Body:(First Formed Ketone Body)
CH3-CO-CH2-COOH Acetoacetic Acid
(Unstable Product)
2)Secondary Ketone bodies:(Derived From Primary Ketone Body)
CH3-CHOH-CH2-COOH -Hydroxybutyric Acid
CH3-CO-CH3
Acetone
(Non-metabolized product)
? True Ketone Bodies:
(Possess Ketone group in their structure)
?Acetoacetate (Unstable)
?Acetone ( Volatile)
Significance Of
Ketogenesis
? Ketogenesis becomes of
great significant during
starvation.
? It improves survival phase of
vital organs.
? Ketone bodies formed by
Ketogenesis serve as an
alternative source of energy
for extra Hepatocytes.
?Brain adapts utilizing
Ketone bodies in
starvation conditions
where there is poor
availability of Glucose.
? After the diet has been
changed to lower blood
Glucose
? After 3 days the Brain gets
25% of its energy from
Ketone bodies
? After about 40 days, this
goes up to 70% energy
source to Brain.
?Thus Ketogenesis provides
energy for vital organs and
?Maintain there minimal
functions during prolonged
starvation
Aim Of Steps Of Ketogenesis
OR
What Happens During The Steps
Of Ketogenesis?
? Ketogenesis takes place to transform
impermeable Acetyl CoA molecules ( which are
impermeable through mitochondrial
membranes) to permeable Ketone bodies.
? This is By:
? Condensation of Acetyl-CoA molecules
? Removal of complex impermeable CoA from
Acetyl-CoA moieties.
? Forming permeable Acetoacetate (Ketone body)
? The main aim to operate
Ketogenesis in Mitochondria
of Hepatocytes is:
?To remove the complex
impermeable CoA from
carbon units of Acetyl?CoA
?Form permeable
Acetoacetate(4C) to mobilize
out of Liver.
? Ketogenesis removes
impermeable and accumulated
Acetyl-CoA out of Liver
Mitochondria .
? Thus steps of Ketogenesis
prevent accumulation of Acetyl-
CoA in matrix of mitochondria.
? Ketogenesis retains and recycle
the CoA pool of Mitochondrial
matrix .
? And the carbon units of Acetyl-
CoA are removed as
Acetoacetate.
? Formation of permeable Ketone
body Acetoacetate
? Significantly removes the
accumulated carbon units of
Acetyl-CoA
? In the form of Acetoacetate
(Ketone body) from Liver
Mitochondrial matrix.
Regulation of Ketogenesis
HMG COA Synthase
is the Regulatory Enzyme
of Ketogenesis
?HMG-CoA Synthase
activity is induced by
increased fatty
acids in the blood.
? CoA-SH levels regulate the
Ketogenesis to retain CoA
pool in Mitochondrial matrix.
?Reduced CoA-SH levels
stimulates HMG CoA Synthase
?Increased CoA-SH levels
inhibits HMG CoA Synthase
qKetogenesis is regulated at three
crucial steps:
q Control of Free Fatty acid mobilization
from Adipose tissue (Lipolysis)
q The activity of Carnitine
Palmitoyltransferase-I in Liver.
q Partition of Acetyl-CoA between the
pathway of Ketogenesis and the Citric
acid cycle by OAA levels.
Regulation of Ketogenesis
Factors Responsible
For Increased Ketogenesis
? Normal y Ketogenesis takes place to
smal extent.
? Ketone bodies are created at
moderate levels in our bodies,
? Such as during sleep and other times
? When no Carbohydrates/Glucose are
readily available in cells.
?The rate of Ketogenesis
and its efficiency directly
depends upon:
?The Insulin activity
?Levels of Cellular Glucose
?Levels of cellular OAA
?Increased and
incomplete oxidation of
Fatty acids increases
Ketogenesis.
? The condition where there
is more cellular Glucose
deprivation
? More is the efficiency of
Ketogenesis.
?Thus conditions which
accumulates excess of
Acetyl ?CoA in
Mitochondrial matrix.
?Divert this Acetyl-CoA for
Ketogenesis.
Which are The Conditions
Which Deprives
Cellular Glucose And OAA
And
Increases The
Rate Of Ketogenesis ?
?Prolonged Starvation
?Diabetes Mellitus
Uncontrolled Condition of
DM: Diabetic Ketoacidosis
?Severe Vomiting
?Toxemia of Pregnancy
? Deprivation of Cellular Glucose
? High rates of Fatty acid Oxidation
? Low levels of cellular Oxaloacetate
? Under utilization of Acetyl CoA in TCA cycle
? Large accumulated amounts of impermeable
Acetyl-CoA in mitochondrial matrix.
? Accumulated Acetyl-CoA diverted for
Ketogenesis and
? Formation of soluble and permeable Ketone
bodies which can be easily mobilized out of the
Mitochondrial matrix.
Inter Relationship
Of
Carbohydrates And Lipid
Metabolism
?Thus low/non availability of
Oxaloacetate in cells in emergency
condition
?Does not oxidize Fatty acid Acetyl-
CoA completely via TCA cycle.
?This results in accumulation of Acetyl
-CoA in Mitochondrial matrix
?Which then activates and diverts
Acetyl-CoA for Ketogenesis.
Fats Burns
In The Flame Of Carbohydrates
MEANS
For Complete Oxidation
Of Fatty Acids
There Needs Presence of
Sufficient Glucose In The Cells
? Fat burns under the flame of
Carbohydrates.
? Complete oxidation of Acetyl-CoA
obtained through Fatty acid
oxidation
? Requires sufficient Oxaloacetate
which is a source from normal
Glucose metabolism.
? Sufficient cellular Glucose (Flame)
keeps the availability of OAA
? To initiate and operate TCA cycle
and completely oxidize the end
product of beta oxidation of Fatty
acid Acetyl CoA to CO2 ,H2O and
ATP.
? The entry of Acetyl CoA into the Citric
acid cycle depends on the availability
of Oxaloacetate.
? The concentration of Oxaloacetate is
lowered
? If Glucose is unavailable (Starvation) or
improperly utilized (Diabetes mellitus).
? Oxaloacetate is normally formed from
pyruvate by Pyruvate Carboxylase (
Anaplerotic reaction).
? In Starvation or Diabetes mellitus
the Gluconeogenesis is activated
and Oxaloacetate is consumed in
this pathway.
? Fatty acids are oxidized
producing excess of Acetyl CoA
which is converted to Ketone
bodies:
?In deprivation of
Glucose
?Acetyl CoA is under
utilized and incomplete
oxidized via TCA cycle.
Why Ketogenesis Occur?
The Main aim for the steps of
Ketogenesis to occur is:
? To remove the complex, impermeable
,accumulated Acetyl CoA in
Mitochondrial Matrix
? By transforming Acetyl-CoA into
permeable Ketone bodies by removing
CoA moiety.
? Maintain the levels of free CoA pool of
Mitochondrial matrix
? During emergency conditions due to
low cellular Glucose.
? There is alternatively increased beta
oxidation of Fatty acids, producing
Acetyl-CoA.
? Deprivation of cellular Glucose also
depletes the levels of Oxalo Acetate
which is an initiator of TCA cycle.
? Low levels of cellular OAA under
utilizes the Acetyl-CoA via TCA
cycle.
? Acetyl-CoA which is obtained by
Fatty acid oxidation is less
utilized via TCA cycle .
? This accumulates impermeable
Acetyl-CoA in the Mitochondrial
matrix.
? To remove the accumulated,
impermeable Acetyl-CoA out
from the Mitochondrial matrix,
there occurs Ketogenesis .
Why Fatty Acids
Are Not Completely Oxidized
In Emergency Conditions?
? Fatty acids in emergency conditions
are not completely oxidized to
CO2,H2O and ATP.
? Fatty acids in emergency undergo
Beta oxidation and produce Acetyl-
CoA
? But the produced Acetyl CoA is not
further completely oxidized via TCA
cycle.
? The main facts to have
incomplete oxidation of Fatty
acids in emergency condition
are :
?Low levels of cel ular Glucose
and Oxaloacetate
What Makes
The Cellular Oxaloacetate
To Get Depleted
In Emergency Conditions?
Remember
?In emergency conditions
where the cellular Glucose is
low
?Oxaloacetate levels also gets
depleted
?Reasons for depletion of cel ular
OAA are:
?Glucose is the main source of
OAA
?OAA is, obtained by Pyruvate
Carboxylase reaction
?Thus low availability of cellular
Glucose brings low production of
OAA from Glucose in cells.
?OAA is an emergency
condition is diverted for
Gluconeogenesis and
transformed to Glucose.
?Which reduces the actual
OAA levels in the cel s.
Remember
?OAA is an initiator of TCA
operation and
?OAA is required for
complete oxidation for
Acetyl-CoA.
Fates Of Ketone Bodies
OR
Ketolysis/Breakdown
Of
Ketone Bodies
OR
Utilization Of Ketone bodies
Fates of Three Ketone bodies
Uses Of Ketone bodies
?Ketone bodies serves as a
special and major source of
fuel/energy
?For certain tissues in
prolonged starvation
phase.
? In the starvation condition
where body has low
Glucose.
? Ketone bodies are used to
generate energy by several
extra hepatic tissues
Fate Of Acetoacetate
?Acetoacetate may be oxidized and serve as
a source of energy to extrahepatocytes.
? If not oxidized to form usable energy,
it is converted to next two Ketone bodies
?Acetone and BHB
?If it is not utilized Acetoacetate excreted
out through urine.
Fate of -Hydroxybutyrate
?It is not technically a Ketone
according to IUPAC
nomenclature.
?It may be used up for energy
source or excreted out through
urine if not used.
Fate Of Acetone
?Acetone is not used as
an energy source,
?But it is instead exhaled
or excreted as waste
through expiration.
Acetone Do not Serve
as Energy Source
?Acetone being volatile ,
is not catabolized and
oxidized
?To liberate energy in the
extra hepatocytes.
Ketolysis
What Is Ketolysis ?
? Ketolysis is breaking and
utilization of Ketone bodies as
energy source
? In the Mitochondrial matrix of
Extra Hepatocytes.
n Ketone bodies have less potential
metabolic energy than the fatty
acids from which they are derived.
n They make up for this deficiency
by serving as "water-soluble lipid
derivatives" that can be more
readily transported in the blood
plasma.
n During Starvation and in the
bodies of uncontrolled Diabetes
mellitus, Ketone bodies are
produced in large amounts
n They become substitutes for
Glucose as the principal fuel for
Brain cells.
Site Of Ketolysis
?Mitochondrial
Matrix of Extra
Hepatic Tissues.
? Thus primary tissues using Ketone
bodies when available are :
?Brain
?Muscle
?Kidney
?Intestine
?But NOT in the Liver
? Ketolysis does not takes place in
Liver
? Due to absence of enzyme
Thiophorase in Liver which is
required for Ketolysis.
n In early phase of starvation
Heart and skeletal muscles
primarily use Ketone bodies
for energy
n Thereby preserving the limited
Glucose and supply it for use
by the Brain.
? Brain which normal y depends
on Glucose and do not have
capacity to use Fatty acids.
? during starvation condition
Brain adapts using Ketone
bodies as major energy source
for its survival
v Heart Muscle and the Renal cortex
use Acetoacetate in preference to
Glucose in physiological conditions.
v The Brain adapts to the utilization
of Acetoacetate during Starvation.
Steps Of Ketolysis
Remember
? Ketone bodies will be broken
and utilized in only those
organs/tissues/ cells
? Which possess at least some
content of Glucose and Oxalo
acetate.
? Ketolysis breaks the Ketone
bodies and releases Acetyl ?
CoA
? The released Acetyl-CoA is
then final y oxidized via TCA
cycle to CO2,H2O and ATPs.
Conversion of Ketone
Bodies to Acetyl-CoA
n Ketone bodies as an energy source, b-
Hydroxybutyrate and Acetoacetate
n Enter mitochondrial matrix of extra
hepatocytes
n Where they are converted to Acetyl
CoA,
n Which is further completely oxidized
by the TCA/ Citric acid cycle.
n b-Hydroxybutyrate is oxidized to
Acetoacetate in a reversible reaction
catalyzed by an isozyme of b-
Hydroxybutyrate Dehydrogenase of
extrahepatocytes.
n Remember that this reaction enzyme
is distinct from the Liver enzyme b-
Hydroxybutyrate Dehydrogenase.
Use Of Succinyl-CoA
For Thiophorase Reaction
In Ketolysis
? An Enzyme Thiophorase of
Ketolysis requires Succinyl-
CoA for its reaction.
? Succinyl-CoA in this step of
Ketolysis is a donor of
Coenzyme A (?CoASH).
Enzyme Thiophorase
Is Natural y
Absent In Liver
nKetone bodies are broken
down only in non hepatic
tissues
nBecause enzyme Thiophorase
is natural y present in al
tissues except Liver.
nIn extrahepatic tissues,
Acetoacetate is activated to
Acetoacetyl-CoA by Succinyl-CoA-
by catalytic activity of Acetoacetate
CoAtransferase/Thiophorase/Succi
nyl CoA Transferase.
nCoA is transferred from Succinyl-
CoA to form Acetoacetyl-CoA.
? Acetoacetate reacts with
Succinyl CoA to form
Acetoacetyl CoA in a
reaction catalyzed by
Succinyl-CoA
Transferase/Thiophorase .
?The Acetoacetyl-CoA is
split to Acetyl-CoA by
Thiolase and oxidized
in the Citric acid cycle.
succinyl-CoA
transferase
Conversion of Acetoacetate to Acetyl CoA.
Significance Of Ketolysis
? Ketone Bodies Serve as a
Fuel for Extrahepatic
Tissues on its oxidation in
extra hepatocytes in
Starvation condition.
Calorific value of
Ketone bodies is
7 Cal/gram
Calculation
Of
Energetics From
Degradation of Ketone bodies
in Peripheral tissue
1.Acetoacetate is oxidized into 2
Acety1 CoA, which enter the Citric
acid cycle.
?Activation of Acetoacetate
consumes 1 ATP , and the total
amount of ATP from metabolism of
2 Acety1 CoA via TCA cycle is 20 ? 1
= 19 ATP
2. Conversion of - Hydroxybutyrate
back into Acetoacetate generates 1
NADH ,
which produces an additional 2.5ATP
total ATP produce = 22ATP)
(19 +2.5) = 21.5 ATP
After entering the electron transport
chain .
Balance and Imbalance
In
Ketone Body Metabolism
? In normal physiological
conditions.
? There occurs balance in
Ketogenesis and Ketolysis
? When the cel ular Carbohydrates and Lipids
are in proper proportionate.
? Then the formation and utilization of Ketone
bodies in the body is balanced and low.
? There is balance in Ketogenesis and Ketolysis
? A very low levels of blood Ketone bodies are
present in normal physiological healthy
condition.
?Normal blood levels of
Ketone bodies is approx.
less than 1 mg%.
Levels Of Ketone Bodies
Increases
As The
Starvation Phase Prolongs
?3 days starvation
[KB]=3mM
?3 weeks starvation
[KB]=7mM
Rate Of Ketolysis
? Rate of Ketolysis in extra
hepatocytes is dependent upon :
?The cel ular levels of Glucose
and Oxaloacetate in extrahepatic
tissues .
?Rate of Ketolysis
decreases
?In more deprived
conditions of cellular
Glucose and OAA.
Imbalance In
Ketone Body Metabolism
? Imbalance in Ketone body
metabolism is
? Increased Ketogenesis and
decreased Ketolysis.
? No/Low Ketolysis in body cells
? Accumulates the Ketone
bodies in the body.
? Which leads to Ketonemia and
Ketonuria.
Ketosis
Ketosis
?Ketosis is a col ective term
used to refer Ketonemia
and Ketonuria .
?Ketosis is a result of
imbalance in Ketone
body metabolism.
?Ketosis is a condition
where there is increased
Ketogenesis and
decreased Ketolysis.
Ketonemia
? Ketonemia is an abnormal
increased levels of
circulating Ketone Bodies in
Blood more than 1 mg%.
Ketonuria
?Ketonuria is an
abnormal excretion of
Ketone bodies in Urine.
? If the blood levels of Ketone
bodies crosses more than the
renal threshold levels of KB
(3mg%) it causes-Ketonuria.
Ketoacidosis
? Ketoacidosis is Acidosis caused due
to increased Ketone bodies.
? Ketoacidosis is a type of Metabolic
Acidosis .
? It is caused due to imbalance in
Ketone bodies metabolism.
? During KETOACIDOSIS
? Excessive build-up of Ketone
bodies results in Ketosis
eventual y
? Leading to a fal in blood pH
due to the acidic Ketone
bodies.
Ketosis (Ketoacidosis)
Acetone odor in the breath
Acetoacetate and Acetone in urine
Biochemical Basis Of Ketosis
?Cel ular Deprivation
Of Glucose
?Low Insulin Activity
Conditions Of Ketosis
Conditions Of Ketosis
? Prolonged Starvation
? Diabetic Ketoacidosis
(Uncontrol ed Diabetes Mel itus)
? Hyperemesis gravidarum
(Severe Vomiting in first trimester )
? Unbalanced diet i.e. high fat, low
carbohydrate diet
? Renal Glycosuria
? Alcoholics after binge drinking
and subsequent starvation
Consequences Of Ketosis
?Ketone bodies
accumulation in the
body
?May result to negative
long term effects.
?Ketosis create more load
on Lungs and Kidneys
?To expire and excrete
out the Ketone Bodies.
? Ketoacidosis lowers blood pH
affects the Enzyme activities
? Deranges the Metabolism
? Affects Normal energy
metabolism
? Affects Water and
Electrolytes Balance
? Increased Ketone bodies in
blood is neutralized by the
alkali reserve (blood buffers
HCO3-)
? Very excess of Ketone bodies in
blood exhaust HCO3- ,this leads
to Metabolic acidosis.
? If Ketone bodies are far high than
the capacity of alkali reserve to
neutralize them they will result in
acidemia ?
? Uncompensated acidosis with a
decrease in blood pH (Acid Base
Imbalance) which is a serious that
results in death if not treated.
Clinical Features Of Ketosis
Acid Base Imbalance
? Metabolic Ketoacidosis
? Reduced Alkali reserve(HCO3_)
? Kussamaul's Respiration
(Acetone Breath)
Water and Electrolytes
Imbalance
? Osmotic Diuresis (Loss of water and
electrolytes along with Ketone bodies)
? Dehydration
? Sodium Loss (Hyponatremia)
? Coma
? Death
Diagnosis Of Ketosis
Detection Of Ketone Bodies
? Volatile Ketone Body ,Acetone is
expired out through Lungs,
? It can be smelled in Ketotic
persons as Acetone breath (With
Fruity odor)
? Ketone bodies excreted in Urine
can be detected by carrying
Rothera's Test on Urine specimen.
? Positive Rothera's Test with
Magenta color ring in the tube
confirms Ketonuria.
?Ketoacidosis is detected
by analyzing :
?The Blood pH,
Bicarbonates.
? A patient with Diabetic Ketoacidosis
shows:
?Urine Benedicts Test- Positive
?Urine Rothera's Test- Positive
? A patient with prolonged Starvation
shows:
?Urine Benedicts Test- Negative
?Urine Rothera's Test- Positive
Management Of Ketosis
?Increasing Cellular Glucose
?Manages condition of
Ketosis.
? In Starvation Oral or
intravenous Glucose infusion
? In Diabetic Ketoacidosis
infuse Insulin dosage with
Check on Serum Potassium
levels.
Prevention Of Ketosis
? Avoiding cel ular Glucose deprivation
prevents Ketosis.
? A Patient of Diabetes mellitus (Type I) to
prevent Ketosis should control his/her
blood Glucose.
? With proper dosage of Insulin and
maintaining cellular Glucose in cells.
Ketogenic Substances
? Substances Promoting Ketogenesis and
increases Ketone bodies are:
?Low Cel Glucose
?Excess Fatty acids
?Ketogenic Amino acids
?High Glucagon
?Low Insulin
Antiketogenic Substances
? Substances inhibiting Ketogenesis and
decreasing Ketone bodies:
?Sufficient Cel ular Glucose
?Glucogenic Amino acids
?Glycerol
?Normal Insulin
Diabetes and
Ketoacidosis
Diabetic Ketoacidosis
? Diabetic Ketoacidosis is an
Immediate complication of severe
uncontrol ed cases of Diabetes
mel itus(Type I/IDDM)
KETOSIS In Diabetes Mellitus
The Absence of Insulin in Diabetes mellitus
? Liver Glucose Metabolism Altered
? inhibition of glycolysis
? activation of fatty acid
? activation of gluconeogenesis
mobilization by adipose tissue
? Deficit of oxaloacetate
? Large amounts of acetyl CoA which can not be
utilized in Krebs cycle
? Large amounts of ketone bodies (moderately strong acids)
? Severe Acidosis (ketosis)
Impairment of the tissue function, most importantly in the central
nervous system
In Diabetic patients events that can lead to ketosis are:
? Relative or absolute deficiency of insulin
? Mobilization of free fatty acids (from adipose Lipolysis)
? Increased delivery of free fatty acids to the liver
? Increased uptake and oxidation of free fatty acids by the liver
? Accelerated production of ketone bodies by the liver
? When there is not enough Insulin in the
blood in cases of IDDM
? Cellular Glucose deprivation affects its
efficient use to produce energy.
? Thus, the body utilizes the Lipids for its
energy.
? Excessive Lipid degradation with low
Glucose contents , leads to ketones build
up in the blood .
? Ketone bodies then spill over into the
urine so that the body can get rid of
them.
? Acetone can be exhaled through the
lungs. This gives the breath a fruity odor.
? Ketones that build up in the body for a
long time lead to serious illness and
coma. (Diabetic Ketoacidosis)
? Ketone bodies Acetoacetate
and Beta Hydroxy Butyrate
are acidic
? When produced in excess over
long periods in Diabetes,
causes Diabetic ketoacidosis.
? In a case of severe Diabetic
Ketoacidosis
? The Ketone bodies in the
blood and urine may reach
Life threatening
concentrations.
? Blood Ketone bodies may be
up to 100 mg%
(Normal1mg%)
? Urinary excretion of Ketone
bodies may be as high as 5 gm
/day.
(Normal 125 mg/day)
Clinical Features OF DKA
Creates Medical Emergency
? Hyperglycemia
? Metabolic Ketoacidosis
? Kussmaul's Respiration
? Severe Dehydration /Water
Imbalance
? Electrolyte Imbalance
? Acid Base Imbalance
? Coma
? Death
Formation, Utilization, and Excretion of Ketone bodies
Lipogenesis
What Is Lipogenesis?
?Lipogenesis is the
biosynthesis of various
forms of Lipids in
human body.
When Lipogenesis Occurs?
?Lipogenesis occurs in a
well fed condition at
Cytosol of body tissues.
Conditions Favoring Lipogenesis
vExcess of Free Excess Glucose
after heavy Carbohydrate
meals.
v Insulin promotes Lipogenesis
Forms Of Lipid
Biosynthesized In
Human Body Tissues
LIPID BIOSYNTHESIS
? Fatty acid Biosynthesis
? Triacylglycerol Biosynthesis
? Cholesterol Biosynthesis
? Phospholipids Biosynthesis
? Glycolipids Biosynthesis
? Eicosanoids Biosynthesis
Where Does Lipogenesis Occur?
Site Of Lipogenesis
?Liver Cytoplasm is the
predominant site for
Lipogenesis.
?Intestine ,Mammary
glands are other tissues
for Lipogenesis
? The endogenously
biosynthesized Lipids in Liver are
? Gathered and mobilized out in
the form of Lipoprotein VLDL to
extrahepatic tissues.
? VLDL carries endogenous
Lipids from Liver to extra
Hepatocytes.
? TAG is stored as reserve
food material in Adipose
tissue in unlimited amount.
Precursors For Lipogenesis
Precursors For Lipogenesis
? Acetyl-CoA serve as a precursor
for Fatty acids and Cholesterol
biosynthesis.
? This Acetyl-CoA comes from
excess and free Glucose Oxidation
in a wel fed condition.
?Phospholipid
biosynthesis needs
Lipotropic factors.
Why Lipogenesis Takes Place?
Reasons For Lipogenesis
? Free excess Glucose cant be stored in
body cells and tissues as it is .
? Free excess Glucose is first converted
and stored in the form of Glycogen
? Storage of Glycogen is limited
? In a well fed condition after limited storage
of Glycogen
? When stil there remains Free excess
Glucose
? This free excess Glucose is Oxidized to
Pyruvate via Glycolysis
? Further Pyruvate to Acetyl-CoA via PDH
complex reaction
? The formed Acetyl-CoA when excess is then
diverted for Lipogenesis.
? Thus Lipogenesis occur in a wel
fed condition
? To transform the free excess
Glucose/Acetyl-CoA in the body
tissues into
? Storage able form of Lipid (TAG).
? TAG in the Adiposecytes can be
stored in unlimited amounts.
Hormonal Influence
On Lipogenesis
? In a well fed condition
? Hormone Insulin stimulates
Lipogenesis.
? Hormone Glucagon inhibits
Lipogenesis.
De Novo Biosynthesis
Of Fatty Acids
?Fatty acid biosynthesis is a
reductive biosynthetic
mechanism.
?To form reduced molecules
of Fatty acid (Palmitate).
? De novo biosynthesis of Fatty
acids is a new biosynthesis of
Fatty acids.
? Using simple carbon units
Acetyl-CoA and NADPH+H+ to
a long chain fatty acids.
? Palmitic acid (16:0) can
be further modified to
higher Fatty acids .
Site For Fatty Acid Biosynthesis
Organs Involved For
Fatty Acid Synthesis
? In humans, Fatty acids are
biosynthesized in Cytosol of:
?Liver (Predominantly)
?Adipose tissue
?Intestine
?Lungs
?Brain
?Renal Cortex
?Mammary glands during lactation
Reductive Biosynthesis
Of Fatty acids
Extra Mitochondrial/Cytosolic
Biosynthesis of Fatty acids
? The biosynthetic pathway of Fatty acids
involves
? The use of reducing equivalents
NADPH+H+ in the reduction steps.
? To form the reduced molecule of fatty
acids,
? Hence it is termed as reductive
Synthesis of Fatty acids.
? Fatty acids biosynthesized are
used up for biosynthesis of :
?Triacylglycerol
?Phospholipid
?Glycolipid
?Cholesterol Ester
?Fatty acids are stored as
Triacylglycerol, especially
in Adipose tissue.
Biosynthesis Of Palmitic Acid/Palmitate
(C16)
Requirements Of
De novo Biosynthesis
Of Fatty acids
? Precursor for Fatty acid
biosynthesis is Acetyl-CoA
Species comparison of fatty acid synthesis
Species
Principal Tissue Site
Carbon Source
Poultry
Liver
Glucose
Human
Liver
Glucose
Pig
Adipose
Glucose
Mouse
Adipose
Glucose
Sheep
Adipose
Acetate
Cattle
Adipose
Acetate
? Requirement of HCO3-
(Bicarbonate Ions) : Provides
CO2 for Acetyl-CoA
Carboxylation Reaction.
? Enzymes Involved:
?Acetyl-CoA Carboxylase
?FAS Multi Enzyme Complex
Coenzyme Required
? Reducing Equivalent :
?NADPH+H+
qThe main source of NADPH+H+ is
mainly by the Pentose Phosphate
Pathway.
?The Malic enzyme activity
converts Malate to Pyruvate which
is another source of NADPH+H+
Production of NADPH+ H+
?NADPH+H+ serves as an
electron donor in the
two reactions
?Involving substrate
reduction in De Novo
Fatty acid biosynthesis.
Who Is The source
Of Acetyl-CoA for Fatty acid
Biosynthesis ?
?Free and Excess Glucose in
a wel fed condition
?Is the major source of
carbon for the De novo
fatty acid biosynthesis.
?Free and excess Glucose
remained after limited
Glycogen storage
?Is used for Acetyl-CoA
production and diverted for
the Fatty acid biosynthesis.
?Glucose is oxidized to
Pyruvate via Glycolysis.
?Pyruvate(3C) is then oxidatively
decarboxylated
?To a high energy compound
Acetyl-CoA (2C)in Mitochondria
by PDH Complex.
? The excess of Acetyl CoA formed
and present in Mitochondrial
matrix
? Is diverted for Denovo
Biosynthesis of Fatty acids.
? 8 molecules of Acetyl-CoA (C2)
are required
? For the biosynthesis of
1 molecule of even carbon
Palmitate (C16).
?Eight Acetyl-CoA's are
involved.
?To grow a Fatty acid
Chain of 16-carbons
Fatty Acyl Synthase (FAS)
Multi Enzyme Complex
For De Novo Biosynthesis
Of Fatty Acids
Fatty Acyl Synthase (FAS) Complex
? FAS is a Multi Enzyme Complex
Used in De Novo Biosynthesis of
Fatty acids.
? Structurally FAS is a Homodimer
? Two alike monomeric subunits
? Linked together in head to tail
fashion (Anti Paral el)
Structural Aspects Of FAS
? FAS is Composed of 8
Components
? 7 Enzymes and 1 Protein
Three Subunits/Domains
Of FAS Complex
1.Condensation Unit
Has 3 Enzymes
? Acetyl Transacylase
? Malonyl Transacylase
? Beta Keto Acyl Synthase
2. Reduction Unit
? ACP- (Acyl Carrier Protein)
? Beta Keto Acyl Reductase
? Dehydratase
? Enoyl Reductase
3. Cleavage /Releasing Unit
? Thioesterase (Deacylase)
ACP Of FAS Complex
? Acyl Carrier Protein (ACP) of FAS
complex is a carrier of growing
Acyl chain
? During De novo biosynthesis of
fatty acids.
The Acyl Carrier Protein
Carrier of Intermediates in Fatty acid synthesis
? Discovered by P. Roy Vagelos.
? ACP is a Conjugated
Protein component of FAS
complex.
? ACP is a part of Reduction
unit of FAS complex.
? 4- Phospho Pantethene serve as a
prosthetic group of ACP.
? 4-Phospho Pantethene is a
derivative of Vitamin B 5-
Pantothenic acid.
? 4 Phosphopantetheine (Pant)
is covalently linked to Serine
hydroxyl of Protein domain of
ACP via a phosphate ester
linkage .
? ACP has ?SH group (Thiol) as
functional group.
? -SH group of ACP is an acceptor of
Acetyl-CoA and Malonyl-CoA
during De novo biosynthesis of a
Fatty acids.
? At the end of Denovo Fatty
acid biosynthesis
? The complete chain of Fatty
acid is linked to ACP of FAS
complex.
?The long flexible arm of
Phosphopantetheine
helps its Thiol
?To move from one active
site to another within
the FAS complex.
Key Player:
Acyl Carrier
Protein(ACP)
"Macro"
CoA, carries
growing fatty
acid chain
via Thioester
ACP vs. Coenzyme A
?Intermediates in synthesis are linked to -SH groups of
Acyl Carrier Proteins (as compared to -SH groups of CoA)
?In terms of
function, ACP is a
large CoA.
Acyl Carrier Protein
Phosphopantetheine
H
H HO CH3
O
HS-CH
ACP
2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-CH2-Ser-
Cysteamine
O
O H H
O
Acyl carrier protein
10 kDa
H
H HO CH3
O
O
HS-CH2-CH2-N-C-CH2-CH2-N-C-C-C-CH2-O-P-O-P-O-CH2
O
Adenine
O
O H H
O
O
O
H
Coenzyme A
O-P-O
OH
OH
FAS Complex Is Coded
By Single Gene
Location Of FAS Complex
?Cytosol
?Extra mitochondrial
Hormones Regulating
FAS Complex
? Insulin- Stimulates FAS Complex
? Glucagon-Inhibits FAS Complex
Functional Parts Of FAS Complex
? FAS complex being dimer has two
functional Units.
?-SH (Thiol) group of Cysteine of
condensation Enzyme Keto Acyl
Synthase.
?-SH (Thiol) group of 4 Phospho
Pantethene of ACP.
Thiol Cysteine residue
Thiol of Phosphopantetheine
? As there are two functional units
? When FAS complex operates at a
time
? There is biosynthesis of two Fatty
acids (Palmitate) molecule.
? Rate of Fatty acid
biosynthesis is high in the
well-fed state.
X-Ray crystal ographic analysis at 3.2 ? resolution
shows the Dimeric Fatty Acid Synthase to have an
X-shape.
Fatty Acid Synthase Complex
Fatty Acid Synthase Complex
Stages And Steps
Of De Novo Biosynthesis
Of Fatty Acids
Three Stages
Of
De novo Biosynthesis
Of Fatty acid
I. Translocation of Acetyl-CoA from
Mitochondria to Cytosol.
I . Carboxylation of Acetyl-CoA to
Malonyl-CoA
I I. Reactions of FAS Complex
Stage I
Translocation of Acetyl-CoA
from
Mitochondria to Cytosol
Transport Of
Mitochondrial Acetyl-CoA
To Cytosol
Since
Fatty Acid Synthesis
Occurs in the Cytosol
Mitochondria Acetyl-CoA
Is to be translocated In Cytosol
Translocation Of Acetyl-CoA
Through
Citrate Shuttle
Citrate Malate Pyruvate
Transport System
Citrate transport
system
? The Mitochondrial Acetyl CoA
is impermeable due to the
complex CoA .
? Impermeable Acetyl CoA is
transformed to permeable
Citrate by Citrate Synthase.
? Citrate is translocated out
in the cytosol.
? Citrate in cytosol is cleaved
by Citrate Lyase to liberate
Acetyl-CoA in cytosol.
?Thus Citrate-Malate-Pyruvate
shuttle provides:
?Cytosolic Acetyl CoA
?Reducing equivalents
NADPH+H+
?For De novo Fatty acid
biosynthesis
?Acetyl CoA from catabolism of
Carbohydrates and Amino acids is
exported from Mitochondria via the
Citrate transport system
?2 ATPs are required during work of
this system.
?Impermeable Acetyl-CoA is
translocated out
?From Mitochondrial Matrix
into Cytosol in the form of
permeable Citrate.
?Acetyl-CoA(impermeable)
produced in the Mitochondria is
condensed with Oxaloacetate to
form Citrate(permeable) by Citrate
Synthase.
? Permeable Citrate is then
transported out into the Cytosol
? Citrate Lyase in Cytosol act upon
Citrate to regenerate Acetyl-CoA
and Oxaloacetate with
consumption of ATP
?Most Acetyl-CoA used
for FA synthesis comes
from Mitochondria.
Stage 2
Carboxylation of
Acetyl-CoA to Malonyl-CoA
In Cytosol
Carboxylation of
Acetyl-CoA(2C)
to
Malonyl-CoA(3C)
By
Acetyl CoA Carboxylase (ACC)
Acetyl-CoA Units
Are Activated To
Malonyl-CoA
For Transfer To Growing
Fatty Acid Chain
Malonyl-CoA Is a High Energy
Compound
With a High Energy Bond In Its
Structure
B. Carboxylation of Acetyl CoA
Enzyme: Acetyl CoA Carboxylase
Prosthetic group - Biotin
?During biosynthesis of 16 C
saturated Palmitic acid
?There requires total 8
molecules of Acetyl-CoA
? During FAS complex Fatty acid
synthetic steps
? Only one molecule of Acetyl-
CoA (C2) enters as it is in the
first step of Third Stage of
Fatty acid biosynthesis.
? Remaining 7 molecules of
Acetyl-CoA are entered in the
form of Malonyl-CoA (C3).
?Thus Seven Molecules of
Acetyl-CoA are
?Transformed to Seven
molecules of Malonyl-
CoA.
? Malonyl-CoA is obtained from
carboxylation reaction of Acetyl-
CoA
? In presence of, enzyme Acetyl
Carboxylase and coenzyme
Biotin and ATP.
vConversion of Acetyl-CoA to Malonyl
CoA , is by catalytic activity of Acetyl
CoA Carboxylase , Biotin and ATP.
vThis is an Carboxylation reaction
which provides energy input.
vTo form still more high energy
compound Malonyl-CoA(C3).
? This carboxylation reaction
after use of high energy ATP
? Builds a high energy bond in
a high energy compound
Malonyl-CoA.
? The input of Acetyl-CoA,
into Fatty acid biosynthesis is
by its Carboxylation to
Malonyl-CoA.
vLater this Malonyl CoA cleaves its high
energy bond and looses CO2 and energy
vThis released energy is used for the
condensation reaction during third stage
of Fatty acid biosynthesis for the initation
and growing of Fatty acid.
?Thus the spontaneous
Decarboxylation of
Malonyl-CoA
?Drives the condensation
reaction of FAS complex.
HCO -
3 + ATP + Acetyl-CoA ADP + Pi + Malonyl-CoA
Acetyl-CoA + HCO -3 + ATP Malonyl-CoA +ADP + Pi
ACC-Biotin
Acetyl CoA Carboxylase (ACC)
ACC
Formation of Malonyl-CoA
Acetyl-CoA Carboxylase
has three activities:
?Biotin carrier Protein
?Biotin Carboxylase
?Trans Carboxylase
Bicarbonate is
Phosphorylated, then picked
up by Biotin
Biotin swinging arm
transfers CO2 to acetyl-CoA
Significance Of
Formation of Malonyl-SCoA
Significance Of
Formation of Malonyl-SCoA
? This Carboxylation reaction is
considered as activation step.
? As the breaking of the CO2 bond of
Malonyl-SCoA releases lot of energy
? That "drives" the reaction forward
for condensation reaction of FAS
complex.
? The high energy bond of
Malonyl-CoA is hydrolyzed
later
? To liberate energy which is
used up for Condensation
reaction of FAS complex.
?Malonyl-CoA serves as
activated donor of Acetyl
groups in FA synthesis.
? Fatty acid synthesis, from
Acetyl-CoA and Malonyl-
CoA,
? Occurs by a series of
reactions catalyzed by FAS
complex.
Stage 3
Reactions Of FAS Complex
During
De Novo Biosynthesis
Of a Fatty Acids /Palmitic Acid
? Initation To Form An Acyl Chain
I.
Loading of Precursors ?Acetyl-CoA at SH-ACP
I .
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
VI. Dehydration Reaction to transform Hydroxyl group to Enoyl
VII. Reduction Reaction to transform Enoyl
VII . Translocation of Butyryl From S-ACP to SH-CE
?Elongation and Growing of Acyl Chain
?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
?Cleavage of Fatty acid/ Palmitate
?By Thioesterase activity to release Palmitate and FAS
Step I-Step I I
Loading Of Precursors
Acetyl CoA and Malonyl-CoA
On FAS Complex
By
Acetyl and Malonyl Transacylases
? The Acetyl-CoA (2C) primer
molecule is first taken up by ?
SH group of ACP of FAS
complex
? To form Acetyl-S-ACP catalyzed
by Acetyl Transacylase.
? Acetyl group from ACP is shifted
to Cysteine-SH of enzyme Keto
Acyl Synthase of FAS complex.
? To form Acetyl-S-Enzyme Keto
Acyl Synthase in presence of
Acetyl Transacylase.
Loading Of Precursor Acetyl CoA
Step 1:
loading of
Acetyl-CoA
onto Fatty
acid
Synthase
? Malonyl-CoA (3Carbon unit)
enters and is taken up by
-SH of ACP of FAS complex
? To form Malonyl-S ACP catalyzed
by Malonyl Transacylase.
Entry Of Malonyl-
CoA
Step 2: loading
of Malonyl-
CoA onto Fatty
acid Synthase
Step IV
Condensation Reaction
Catalyzed By
Beta Keto Acyl Synthase
To Generate
Keto group
At Beta Carbon Atom
Step 2: Condensation
v Reaction of Malonyl
group with Acetyl
group to form
Acetoacetyl- ACP
v Loss of CO2 and energy
from decarboxylation
of Malonyl-CoA.
? The Malonyl Group is
decarboxylated releasing
CO2 and high energy
? Which is used for bond
building and condensation
reaction.
? During condensation reaction
there is linking of 2C units of
Acetyl and 2C units of
decarboxylated Malonyl carbon
units
? To form a 4 C Beta Keto Butyryl
ACP/ Keto Acyl ACP.
Step V
Reduction Reaction
By
Keto Acyl Reductase
To
Generate Beta Hydroxyl group
Step 3: Reduction of beta Keto
group to form beta Hydroxyl group
Reduction Of Keto Acyl- ACP
? Keto Acyl- ACP is reduced to
Hydroxy Acyl- ACP
? In presence of reducing
equivalents NADPH+H+ and
Enzyme Keto Acyl Reductase.
Step VI
Dehydration Reaction
By
Dehydratase
To
Develop Double Bond
Step 4: Dehydration Reaction
? Hydroxy Acyl- ACP is
dehydrated to Enoyl CoA/
? Unsaturated Acyl ACP
by the catalytic action of
Dehydratase.
Step VI
Reduction Reaction
By
Enoyl-CoA Reductase
To Generate
Saturated Bond
Step 5: Reduction of double bond to Single
bond
? ? Unsaturated Acyl ACP is
reduced to Butyryl ?S-ACP
? By NADPH+ H+ and enzyme
Enoyl Reductase.
Overview of
Assembly Stage
4 steps:
Condensation
Reduction
Overview of
Assembly Stage
Dehydration
Reduction
Step VI I
Translocation Of Butyryl-S CoA to
SH group of Condensing Enzyme
Beta Keto Acyl Synthase
Transfer of Butyryl Chain to SH group
of Beta Keto Acyl Synthase
Elongation and Growing
Of Fatty Acid Chain
To Elongate the Fatty Acid Chain
To 16 Carbon Palmitate
There Should Be Entry
Of
6 More Molecules of
Malonyl CoA
By Six Time Repetitions of
Steps I I-VI I
1 Malonyl-CoA entry each
Time
Next cycle begins
?Another
Malonyl group is
linked to ACP
Repetitions Of
6 More Cycles
With 5 Steps
? Following transfer of the
growing fatty acid from
Phosphopantetheine to the
Condensing Enzyme's Cysteine
sulfhydryl.
? the cycle begins again, with
another Malonyl-CoA.
? Elongation of Fatty Acyl
chain occurs by addition of
Malonyl-CoA after every
cycle.
? Every time a new Malonyl ?
CoA enters and taken up by
SH-ACP.
? There are total 7 cycles to utilize
? 1 Acetyl-CoA and 7 molecules of
Malonyl-CoA and
? Elongate the Fatty Acid Chain to
16 Carbon Palmitate.
Remember
? At Each turn one Molecule of Malonyl
CoA enters
? Accepted by ACP-SH to form Malonyl ?
SACP.
? Then the repetitions of Condensation
,Reduction , Dehydration and
Reduction Reactions takes place.
? Decarboxylation of Malonyl-
CoA and
? Reducing power of
NADPH+H+ drive fatty chain
growth.
? Butyryl group (C4) is shifted to
SH of Cysteine of Keto Acyl
Synthase.
? SH of ACP is free for accepting
the second molecule of
Malonyl CoA to form Malonyl-S
-ACP.
? The steps of Condensation
,Reduction, Dehydration and
Reduction repeats.
? The aim of these steps is to
convert a C=O group to CH2
group at carbon of growing
Acyl chain.
?After the completion of
total 7 cycles
?There is Palmitate
synthesized and is carried
by S-ACP of FAS
complex(Palmitoyl-S-ACP)
Cleavage Of Completely
Biosynthesized Palmitate
From ACP of FAS Complex
By Catalytic Activity Of Thioesterase
To Release
Free Palmitate and FAS Complex
? The Cleavage enzyme
Thioesterase cleaves the
Thioester linkage and
? Releases free Palmitic acid
carried by S-ACP of FAS complex.
? Since the FAS complex is a dimeric
unit having two functional units.
? During its operation at a time two
molecules of Palmitic acid are
biosynthesized and released.
Fatty Acyl Synthase
The Steps in the De Novo biosynthesis of fatty acid
Step 1: Loading Reactions
Step 2: Condensation Rxn
Condensation reaction
Step 3: Reduction
Reduction Reaction
Step 4: Dehydration
Dehydration
Step 5: Reduction
Reduction
Step 6: Next condensation
Repetitions Of 7
Cycles
Termination of
Fatty Acid
Acyl-CoA
Synthesis
synthetase
Final reaction of FA synthesis is Cleavage
? Palmitoyl-ACP is hydrolyzed by a Thioesterase
Overal Reaction of Palmitate Synthesis from Acetyl
CoA and Malonyl CoA
Acetyl CoA + 7 Malonyl CoA + 14 NADPH + 14 H+
Palmitate + 7 CO2 + 14 NADP+ + 8 HS-CoA + 6 H2O
Summary based on Malonate as an input:
Acetyl-CoA + 7 Malonyl-CoA + 14 NADPH
Palmitate + 7 CO2 + 14 NADP+ + 8 CoA
Fatty acid synthesis occurs in the cytosol. Acetyl
-CoA generated in mitochondria is transported
to the cytosol via a shuttle mechanism involving
Citrate.
Stoichiometry for Palmitic Acid Synthesis
Diagrammatic View of
Fatty Acid Biosynthesis
Energetics Of De Novo Synthesis
Of Fatty Acids
?De Novo Fatty acid
biosynthesis is an
Anabolic process
involving use of ATPs.
? Total 23 ATPs are utilized
for the biosynthesis of one
molecule of Palmitate.
?2 ATPs are used for 1 Acetyl-CoA translocation
through Citrate transport system
? For 8 Acetyl CoA translocation uses 16 ATPs
?1 ATP each is used for Acetyl CoA Carboxylation
to Malonyl CoA.
? To form 7 Malonyl CoAs 7 ATPs are utilized.
? 16+7 =23 ATPs Net utilized
Regulation Of Fatty Acid Biosynthesis
The Enzyme Acetyl Carboxylase
Is a
Regulatory ,Key Enzyme
Of
De Novo Fatty acid Synthesis.
? The Committed Step of Fatty Acid Synthesis
? Carboxylation of Acetyl CoA to Malonyl CoA
? By Acetyl CoA Carboxylase - Biotin
?Carboxylation of Acetyl-CoA
to form Malonyl-CoA
?Is an Irreversible, committed
step in Fatty acid biosynthesis
Modes Of Regulation
Of Acetyl CoA Carboxylase
of FA Biosynthesis
Acetyl-CoA Carboxylase is regulated
by 3 modes:
1. Hormonal Influence
2. Al osteric Control
3. Covalent Modification
1. Hormonal Influence
? ACC is an Inducible Enzyme:
?Induced by Insulin
?Insulin activates ACC
?Repressed by Glucagon
?Glucagon inhibits ACC
2. Al osteric Modifiers
?Citrate Activates Acetyl-CoA
Carboxylase (Feed Forward)
?Fatty Acyl-CoAs inhibit Acetyl-
CoA Carboxylase
Al osteric modification of
Acetyl-Co A Carboxylase
?Activated by: Citrate
?Inhibited by: Long Chain
Fatty Acid
? Body with high levels of cel ular
Citrate
? Stimulate De novo biosynthesis of
Fatty acids.
? Body on a high fat diet experience
little if any de novo fatty acid
synthesis.
3. Covalent Modification Of
Acetyl-CoA Carboxylase
? ACC is Activated by :
Dephosphorylation
? ACC is Inhibited by:
Phosphorylation
Covalent Modification Of ACC
Covalent Regulation OF
Acetyl CoA Carboxylase
? Activation of ACC
? In a wel Fed state
?Insulin induces Protein Phosphatase
?Activates ACC by De phosphorylation
? Inactivation of ACC
? In a Starved state
?Glucagon increases cAMP
?Activates Protein kinase A
?Inactivates ACC by Phosphorylation
Acetyl-CoA Carboxylase
Control of Fatty Acid Synthesis
Biosynthesis and Degradation
of
Fatty Acid
are
Reciprocal y Regulated
?During Starvation
?Epinephrine & Glucagon Stimulate
Lipolysis
?Brings degradation of FA
?Wel Fed state
v Insulin inhibits Lipolysis
vInsulin Stimulates Fatty acid
biosynthesis.
? ACC also influences degradation of Fatty
acids.
?Malonyl CoA inhibits Carnitine
Acyltransferase I activity.
?This limits Beta oxidation of Fatty acids
in Mitochondrial Matrix.
Reciprocal Control
Overview of Fatty Acid Metabolism:
Insulin Effects
? Liver
? Increased fatty acid
synthesis
? Glycolysis, PDH, FA
synthesis
? Increased TAG synthesis
and transport as VLDL
? Adipose
? Increased VLDL
metabolism
? lipoprotein lipase
? Increased storage of
lipid
? Glycolysis
Overview of Fatty Acid Metabolism:
Glucagon/Epinephrine Effects
? Adipose
? Hormone-sensitive
lipase Increased
? Increased TAG
mobilization
? Increased FA
oxidation
? All tissues Except
CNS and RBC
Post-Synthesis Modifications
Of
Biosynthesized Fatty Acids
? C16 Saturated fatty acid (Palmitate) is the
product which may undergo:
?Elongation
?Unsaturation
?Incorporation to form
Triacylglycerols
?Incorporation into Acylglycerol
phosphates to form
Phospholipids
Chain Elongation Of Fatty Acids
Occurs In
Mitochondria
And
Smooth Endoplasmic Reticulum
Elongation Of Fatty Acids
In Microsomes /Mitochondria
To
Synthesize Long Chain Fatty Acids
? Palmitate biosynthesized by De
Novo Biosynthesis in Cytosol by
the activity of FAS Complex
? Is further elongated to more higher
Fatty acid either in Mitochondria
/Endoplasmic reticulum.
Mitochondrial Chain Elongation
? Here Acetyl-CoA is successively
added to Fatty acid chain lengthened
? In presence of reducing equivalents
NADPH+ H+
? The steps are almost reversal of Beta
Oxidation of Fatty acids.
Microsomal Chain Elongation Of Fatty
Acid
? This is more predominant way of
Fatty acid Chain Elongation.
? It involves successive addition of
Malonyl-CoA with the
participation of NADPH+ H+ and
enzyme Elongases.
Elongation of Chain (Two Systems)
R-CH2CH2CH2C~SCoA
Malonyl-CoA*
O
(cytosol)
HS-CoA
OOC-CH2C~SCoA
CH3C~SCoA
O
CO
O
2
Acetyl-CoA
R-CH
(mitochondria)
2CH2CH2CCH2C~SCoA
O
O
1 NADPH
NADH
Elongation systems are
2 - H
found in smooth ER and
2O
mitochondria
3 NADPH
R-CH2CH2CH2CH2CH2C~SCoA
O
Synthesis Of Unsaturated
Fatty Acids
Mammals can Biosynthesize
Long Chain And Unsaturated
Fatty acids
Using Elongation And
Desaturation
Desaturation of Fatty Acid Chain In
Microsomes
? Enzyme Fatty Acyl-CoA Desaturase
which is a Flavoprotein
? Helps in creating double bonds and
forming Mono Unsaturated Fatty
acids.
? Palmitic acid and Stearic acid
on Desaturation
? Forms corresponding MUFAS
Palmitoleic and Oleic acid
respectively.
? Human body lack the ability to
introduce double bonds beyond
carbon 9 and 10 of Fatty acids.
? Hence body cannot biosynthesize
Linoleic and Linolenic acid and
become dietary essential Fatty acids.
? However Linoleic Acid by
Chain Elongation and
Desaturation
? Forms Arachidonic acid in
Human body.
Palmitic acid
modifications
Cell makes a pool of
palmitic acid that it can
elongate and/or
desaturate in the ER.
Elongation system is
very similar to synthesis:
2C units added from
malonyl-CoA.
Palmitate
Desaturase
16:0 Elongase
Palmitoleate
Stearate
16:1(9)
18:0 Desaturase Permitted
Oleate
transitions
18:1(9)
in mammals
Essential
fatty acid
Desaturase
Linoleate
Desaturase
18:2(9,12)
-Linolenate
-Linolenate
Desaturase
18:3(6,9,12)
18:3(9,12,15)
ElongaseEicosatrienoate
Other lipids
Desaturase20:3(8,11,14)
Arachidonate
20:4(5,8,11,14)
Differences Between
Beta Oxidation Of Fatty Acid
And
De Novo Biosynthesis Of Fatty Acids
The Biosynthesis and Degradation
Pathways are Different
?The major differences
between Fatty acid
breakdown and
biosynthesis are as:
Beta Oxidation
De Novo Biosynthesis
Palmitic acid Pathway Palmitic acid Pathway
Catabolic /Oxidative
Anabolic /Reductive
Occurs In Mitochondria Occurs In Cytosol
Acetyl CoA is an end
Acetyl CoA is a precursor
product
Beta Carbon CH2 is
Beta Carbon C=O is
transformed to C=O
converted to CH2
Generates 106 ATPs
Utilizes 23 ATPs
Coenzymes FAD and
Coenzymes NADPH +H+ is
NAD+ are involved
involved
CoA is an Acyl Carrier ACP is an Acyl Carrier
Fatty Acid Synthesis
Fatty Acid Beta Oxidation
? C=O -CH2
? CH2 C=O
Triacylglycerol (TAG) Biosynthesis
Site For TAG Biosynthesis
? TAG biosynthesis predominantly
occurs in Liver and Adipocytes
TAG Biosynthesis
Takes Place In
Smooth Endoplasmic Reticulum
? TAG biosynthesis takes place after De
Novo Biosynthesis of Fatty acids.
? Fatty acids and Glycerol are activated
before TAG biosynthesis.
? Fatty acids are activated to Acyl CoA by
Thiokinase
? Glycerol is activated to Glycerol-3-
Phosphate by Glycerol Kinase.
? An Acyl chain is transferred to
Glycerol by Acyl Transferase
producing Lysophosphatidic
acid.
? Lysophosphatidic acid is
transformed to Phosphatidic
acid on addition of one more
Acyl chain.
? Phosphate group is removed
from Phosphatidic acid to
generate Diacylglycerol.
? The addition of third Acyl chain
to Diacylglycerol finally results
in Triacylglycerol.
? Usually a mixed type of TAG is
synthesized in the body.
Triacylglycerol Synthesis
Phospholipid Biosynthesis
Glycerophospholipid Synthesis
? Glycerophospholipids are
biosynthesized from
Phosphatidic acid and
Diacylglycerol.
? These are also intermediates of
TAG biosynthesis.
Synthesis OF Lecithin and Cephalin
? Nitrogenous bases Choline and Ethanolamine
are activated by CTP
? To form CDP-Choline and CDP-Ethanolamine.
? These then added to Phosphatidic acid to
form Lecithin and Cephalin respectively.
? Addition of Serine /Inositol to
Phosphatidic acid forms
Phosphatidyl Serine and
Phosphatidyl Inositol
Degradation Of Phospholipids
By Phospholipases
OR
Different Types Of Phospholipases
Cholesterol Metabolism
? Cholesterol is a C27
compound.
? Cholesterol has a parent
nucleus Cyclo Pentano
Perhydro Phenantherene Ring.
Two Forms Of Body Cholesterol
?Free Cholesterol is a
derived Lipid(30%)
?Cholesterol Ester is a
simple Lipid and a body
Wax. (70%)
Cholesterol
? Cholesteryl Ester is a
storage and excretory
form of Cholesterol which
is found in most tissues.
Functions Of Cholesterol
Body Cholesterol Is An Essential
? Component of Biomembranes
? Nerve Impulse Conduction
? Precursor for:
?Steroidal Hormone biosynthesis
?Bile acid/Bile Salts
?Vitamin D
?Remember Cholesterol
is not an energy
producing Lipid.
Sources Of Body Cholesterol
Endogenous And Exogenous
Sources Of Body Cholesterol
? About 1 g/day originates by biosynthesis
? About 0.3 g/day extracted from food
?80% Endogenously produced by
the Liver (0.8 gram/day)
?20% Exogenously comes from the
digestive tract(0.3 gm/day)
? Assume 400 mg is an intake of
dietary Cholesterol per day
? It absorb about 50% Cholesterol
? 200 mg is absorbed from GIT
? 800 mg of Cholesterol is from de
novo synthesis
Dietary Cholesterol
(Animal Sterol)
? Animal products ? eggs
? Animal Brain
? Ghee
? Cheese
Cholesterol Biosynthesis
Is
Endogenous Source Of Body
Cholesterol
Amount Of Cholesterol Biosynthesis
? Endogenously about 1 gm/day
of Cholesterol is biosynthesized.
? Ingestion of excess of
Carbohydrates elevates
Cholesterol biosynthesis.
Conditions Favoring
For
Cholesterol Biosynthesis
? Biosynthesis of Cholesterol takes
place:
?In a wel fed condition
?In excess of free cel ular Glucose
?On stimulation of Insulin
qThe amount of Cholesterol
biosynthesis depends upon
qAvailability of Acetyl-CoA
obtained from Glucose
metabolism in a well fed
state.
? Increased free and excess of
cellular Glucose
? Increases the rate of endogenous
Cholesterol biosynthesis
Cholesterol Synthesis
Simplicity to Complexity
? Al the C27 carbon units of
Cholesterol Structure are
biosynthesized using
? The 2 carbon Acetyl-CoA
units ,obtained from
Glucose metabolism.
Site Of Cholesterol Biosynthesis
Organs and Cel ular Site
For
Cholesterol Biosynthesis
Organs Involved For Cholesterol
Biosynthesis
? Liver (80% )
? Intestine (10%)
? Skin (5%)
? Adrenal Cortex
? Ovaries , Testes , Placenta
? Arterial walls (To some extent)
? Cholesterol Synthesizing Enzymes
are partly located in:
?Cytoplasm
?Endoplasmic Reticulum
Requirements For Cholesterol
Biosynthesis
Requirements For Cholesterol
Biosynthesis
? Metabolic Precursor- Acetyl CoA
(Obtained from excess Glucose
metabolism)
? Enzymes ,Coenzymes and Cofactors
? 16 NADPH +H+ (Through HMP Shunt)
? 36 ATPs
Translocation Of Acetyl CoA
From
Mitochondrial Matrix
To
Cytosol
? Cholesterol is biosynthesized
from Cytosolic Acetyl CoA
? Which is transported from
Mitochondria via the Citrate
transport system.
Stages Of Cholesterol Biosynthesis
? Biosynthesis of Cholesterol is a
very complex process
? To understand divided in 5 Stages
? Requires more than 25 steps.
? Stage 1.
? Acetyl-CoA forms HMG-CoA and Mevalonate.
? Stage 2.
? Mevalonate forms Active Isoprenoid units(C5)
? Stage 3.
? 6 Isoprenoid units form Squalene (C30)
? Stage 4.
? Squalene is converted to Lanosterol
? Stage 5.
? Lanosterol is converted to Cholesterol(C27)
Overview/Outline of Cholesterol Synthesis
Initial Activation Steps in Cholesterol Synthesis
Formation of a C10 intermediate GPP
Formation of C15 and C30 intermediates
? Michael Palmer 2014
Squalene cyclization yields the first sterol
intermediate
Demethylation, desaturation and saturation steps
convert lanosterol to cholesterol
UV-dependent synthesis of Cholecalciferol
Stage I
Synthesis Of HMG CoA
and
Mevalonate
It starts by the condensation of
three molecules of Acetyl
CoA(C2) with the formation of
HMG CoA (C6) by HMG CoA
Synthase (As like In Ketogenesis)
HMG CoA is Reduced to Mevalonic acid (C6)
by reaction requiring NADPH+H+ and enzyme
HMG CoA Reductase.
Two molecules of NADPH are consumed in
the reaction.
Stage 2
Formation Of Isoprenoid Unit
Isopentenyl Pyrophosphate (IPP)
? Mevalonate in three subsequent
steps is
?Phosphorylated with ATPs
?Dehydrated and
?Decarboxylated
? To form Isoprenoid unit(C5)-
Isopentenyl pyrophosphate(IPP).
Isomerization Of IPP To DPP
? Isopentenyl Pyrophosphate
(IPP-C5) is isomerized to
Dimethylal yl
Pyrophosphate (DPP-C5)
with the Isomerase activity
Stage 3
Synthesis Of Squalene (C30)
Formation Of
Geranyl Pyrophosphate
(GPP-C10)
?IPP (C5) and DPP (C5) get
condensed to form
Geranyl Pyrophosphate
(GPP-C10)
Formation OF
Farnesyl Pyrophospate
(FPP- C15)
? 1 molecule of GPP condenses with
1 molecule of IPP to form Farnesyl
Pyrophospahte (FPP-C15)
Conversion Of
FPP(C15) to Squalene (C30)
? Two molecules of FPP get
condensed to generate Squalene.
? At smooth Endoplasmic
Reticulum with the catalytic
activity of Squalene Synthase
Coenzyme NADPH+H+ and
Cofactors Mg , Mn and Co
Sage 4
Conversion Of Squalene To Lanosterol
Stage 5
Transformation Of
Lanosterol To Cholesterol
? Lanosterol is converted to
Cholesterol with many
sequential steps
? With an intermediates
Zymosterol and Desmosterol
Uses Of Body Cholesterol
? Cholesterol after its biosynthesis
may serve as precursor for:
?Steroidal Hormones
?Bile Acids
?Vitamin D
Fates Of Body Cholesterol
? Cholesterol in human body is component of various
biomembranes of cells.
? Cholesterol helps in nerve impulse conduction
? Cholesterol is a precursor for
? Bile acids
? Vitamin D
? Steroidal Hormones-
? Aldosterone
? Estrogen
? Progesterone
? Testosterone
Bile Acids Formed From Cholesterol
? Primary Bile Acids:
? Cholic Acid
? Cheno Deoxy Cholic Acid
? Secondary Bile Acids:
? Glycocholic Acid
? Taurocholic Acid
? De- Oxycholic Acid
? Lithocholic Acid
Bile acids are Derived from Cholesterol
? Bile acids synthesized from
Cholesterol in the Liver are
carried through bile
? Released into the intestine and
reabsorbed in the Jejunum and
Ileum.
Bile Acids are Transformed
To
Bile Salts
Role Of Bile Salts
? Bile Salts are effective detergents
? They are biosynthesized in the Liver
? Stored & concentrated in the Gallbladder
? Bile salts in Intestine facilitates in
digestion and absorption of intraluminal
lipids
? Through formation of emulsions and
mixed micel es.
Fate of Bile Salts
Fates of Cholesterol
Diet
De novo synthesis
Cholesterol synthesized
in extrahepatic tissues
Liver cholesterol
pool
Secretion of HDL
Free cholesterol
Conversion to bile salts/acids
and VLDL
In bile
Regulation Of
Cholesterol Biosynthesis
HMG-CoA Reductase
? Is the regulatory/ key enzyme
of Cholesterol Biosynthesis.
? The enzyme is stimulated and
inhibited as per the
requirement of bodies need.
?The enzyme HMG-CoA
reductase has half-life of 3 hrs.
?Degradation of HMG-CoA
reductase depends on
Cholesterol levels.
Modes Of Cholesterol Regulation
?Hormonal Influence
?Covalent Modification
?Feedback Inhibition
Hormonal Regulation
? Insulin In wel fed state:
?Stimulates and increases HMG
CoA Reductase
?Increases Cholesterol
Biosynthesis
? Glucagon and Glucocorticoids in
emergency states:
?Inhibits HMG CoA Reductase.
?Decreases Cholesterol
Biosynthesis.
Covalent Modification
Of
Regulatory Enzyme
HMG CoA Reductase
Phosphorylation
And
Dephosphorylation
Of
HMG CoA Reductase
? Short-term regulation of
Cholesterol biosynthesis is by
? Phosphorylation &
dephosphorylation of Key
enzyme HMG CoA Reductase
? Phosphorylated ?HMG CoA
Reductase- Inactive Form
? Dephosphorylated-HMG CoA
Reductase- Active form
HMG CoA Reductase - Phosphorylation
HMG CoA Reductase ? OH
HMG CoA Reductase ? P
(active)
(inactive)
AMP-Activated
Protein Kinase (high activity)
(+)
phosphatase
AMP
kinase
(+)
(+)
AMP-Activated
increase cAMP
insulin
Protein Kinase
(low activity)
Glucagon/epi
?Under influence of Hormone Glucagon
?HMG CoA Reductase is Phosphorylated by
cAMP-dependent Protein Kinases.
?Phosphorylation of the Enzyme
inactivates HMG-CoA Reductase
?This inhibits Cholesterol Biosynthesis.
?Glucagon, Sterols,
Glucocorticoids & low
ATP levels
?Inactivate HMG-CoA
Reductase.
?Under influence of Hormone
Insulin
?HMG CoA Reductase is
Dephosphorylated
?Which activates HMG-CoA
Reductase.
?This increases Cholesterol
Biosynthesis.
? Insulin, Thyroid hormone,
high ATP levels
? Activate the key enzyme
HMG-CoA Reductase.
Feed Back Inhibition
? Sufficient amounts of body
Cholesterol regulate its
biosynthesis
? By feed back inhibition of
Enzyme HMG CoA Reductase.
? Ingestion of Cholesterol inhibits
endogenous cholesterol synthesis
(control exerted at both transcriptional
and translational levels).
? Gene expression (mRNA production) is
control ed by Cholesterol levels
Cholesterol Synthesis
Transcription Control
? Rate of HMG-CoA Reductase
mRNA synthesis is control ed
? By Sterol Regulatory Element
Binding Protein (SREBP)
Competitive Inhibitors Of
Cholesterol Biosynthesis
? Drugs like Statins- Lovastatin ,Simvastatin
? Competitive inhibitors of key Enzyme HMG
CoA Reductase of Cholesterol biosynthesis.
? Decreases Endogenous Cholesterol
Biosynthesis
Lovastatin Inhibits Cholesterol
Biosynthesis
? Lovastatin (Mevinolin) blocks HMG-CoA
Reductase activity and prevents biosynthesis
of Cholesterol.
? Lovastatin is an (inactive) Lactone
? In the body, the Lactone is hydrolyzed to
Mevanolinic acid, which is a competitive
inhibitor of HMG CoA reductase.
Drugs Lowering Cholesterol
? Statins ?
decrease HMG
CoA Reductase
activity
"Statins" Competitively Inhibit HMG-CoA Reductase
Effects Of "Statins"
(HMG-CoA Reductase Inhibitors)
? Action: Competitively inhibits HMG-CoA reductase, the key enzyme for de
novo cholesterol biosynthesis.
? Effects Of Statins in Human body:
? Cells express more LDL receptors
? Decreases serum LDL levels
? Increased HDL levels
? Increased HDL/LDL ratio
? Suppresses production of VLDL in Liver
? Advantages: Specific; Effective; Well-tolerated.
? Disadvantages: Hepatotoxicity; myopathy; most expensive; contradicted
in pregnant and nursing women.
Bile salts inhibit the
intestinal HMG CoA
Reductase.
Drugs Inhibitors of Intestinal Cholesterol uptake
Cholesterol Transport
Lipoproteins Involved In Cholesterol
Transport In Blood
?Chylomicrons
?LDL
?HDL
? Chylomicrons transport the
dietary Cholesterol
? From intestine to Liver through
lymph and blood
?LDL transports
Endogenous Cholesterol
?From Liver to Extrahepatic
tissues.
? HDL transports, Cholesterol
for its excretion
? From Extrahepatic tissues to
Liver.
Cholesterol Esterification
? In human body Cholesterol is present in
two forms:
?Free Cholesterol (30%)
?Esterified Cholesterol (70%)
? Cholesterol esterification is by enzyme
ACAT and LCAT activity.
? Cholesterol when has to get
excreted out of the body
? It gets esterified to Cholesterol
Ester and transported for its
excretion.
Cholesterol Esterification
LCAT
(Lecithin: Cholesterol Acyltransferase)
Formation of Cholesterol Esters in Lipoproteins
? Acyl-CoA: Cholesterol Acyl
Transferase (ACAT) is an ER
membrane protein
? ACAT transfers fatty acid of CoA to
C3 Hydroxyl group of Cholesterol
? Excess Cholesterol is stored as
Cholesterol esters in cytosolic lipid
droplets
? The LCAT activity is
associated to Lipoprotein
HDL.
? HDL is responsible for
transporting of Cholesterol
Ester from extra hepatocytes
to Liver for its excretion.
Cholesterol Degradation
and Excretion
? About 1 gram of Cholesterol is
catabolized and excreted out
of body via Bile.
? Cholesterol is mostly converted
to Bile acids and Bile salts and
excreted.
?Thus Cholesterol is
excreted in the form of
Bile acids and Bile salts.
? Bile acids , Bile Salts and
Cholesterol are carried through
bile to intestine for its excretion.
? Thus half of the body Cholesterol
is degraded to Bile acids and
excreted through feces.
? Cholesterol is modified by
intestinal bacterial flora to
? Cholestenol and
Coprostenol which are then
excreted out in feces.
? A person is healthy when there is
a perfect balance between
?Cholesterol Biosynthesis
?Cholesterol Utilization
?Cholesterol Excretion
? This minimizes the chances of
Cholesterol deposition in blood
and tissues.
Note
vIncreased intake of dietary
Cholesterol
vDecreases absorption of
Cholesterol
Blood Cholesterol
And Its
Clinical Significance
Adult Reference Ranges
For Lipid Profile
ANALYTE
REFERENCE RANGE
Total cholesterol
140-200 mg/dL
HDL cholesterol
40-75 mg/dL
LDL cholesterol
50-130 mg/dL
Triglyceride
60-150 mg/dL
1131
OPTIMAL CHOLESTEROL LEVELS
Blood Cholesterol is associated to
Lipoproteins in 2 forms:
v Free cholesterol (30%)
v Esterified Cholesterol (70%)
Classification of
Plasma Cholesterol Concentrations
Total cholesterol
Classification
(mg/dl)
< 200
Desirable
200 - 239
Borderline
> 240
High
HDL Cholesterol
Less than 40 mg/dl
Low level. A major risk factor for CAD
40 to 59 mg/dl
The higher the level the better
60 mg/dl and above
High level. Considered protective against CAD
LDL Cholesterol
? Less than 100 mg/dl Optimal
? 100 to 129 mg/dl Near or above optimal
? 130 to 159 mg/dl Borderline high
? 160 to 189 mg/dl High
? 190 mg/dl and above Very high/ BAD
Cholesterol
Hypercholesterolemia
Causes, Conditions And
Consequences
Hypercholesterolemia
?Abnormal high levels of
Cholesterol more than the
reference range in blood
circulation is termed as
Hypercholesterolemia.
Conditions Of Hypercholesterolemia
? Diabetes mellitus
(Increased Intake /Biosynthesis )
? Nephrotic Syndrome
(Defective Lipoprotein metabolism which is not internalized)
? Obstructive Jaundice
(Bile duct obstruction and regurgitation of Bile in Blood)
? Hypothyroidism
(Decreased Catabolism and Excretion)
Inherited Hypercholesterolemia
? Inherited Hypercholesterolemia is a
genetic cause
? Caused due to defective LDL
receptors on tissues.
? Increases LDL ?Cholesterol in blood
Consequences Of
Hypercholesterolemia
? Increased risk of Atherosclerosis
? Stimulates plaque/thrombus
formation
? May occlude arteries and
? Leads to tissue infarction
? Infarction is irreversible
damage to tissues due to
absence of Oxygen and
Nutrient.
? Infarction of Brain is Stroke
? Infarction of Heart is MI
Hypocholesterolemia
?Abnormal low levels of
Cholesterol in blood
circulation is termed as
Hypocholesterolemia.
Conditions Of Hypocholesterolemia
?Malnutrition
?Malabsorption
?Hyperthyroidism
?Pernicious Anemia
?Hemolytic Anemia
?Liver Disorders
Consequences of High Cholesterol
MORTALITY RELATED
DUE TO
HIGH CHOLESTEROL
? 1 cause of death: Cardio-vascular diseases
? 3 cause of death: Cerebro-vascular
diseases
? 1 + 3 = ~ 40% of al deaths
(Higher risk for Alzheimer & Chronic Liver
disease)
FACTORS INFLUENCING CHOLESTEROL LEVELS
? Diseases :
?Hypothyroidism
?Diabetes mellitus
? Lifestyle (Exercise, Stress, Smoking)
? A Family History-Genetic
defects
? Diet- High Fat and Carb diet
?Age
?Weight- Obese
?Gender (Men, Menopause)
HDL cholesterol levels lower than
<40 mg/dl)
increase a person's risk of
developing coronary artery
disease, especially in people who
also have high total cholesterol
levels.
? HDL Cholesterol levels
greater than 100 mg/dl
?Also increase the risk in
developing coronary artery
disease and Stroke.
CHOLESTEROL PROFILE
IMPROVEMENT STRATEGY
vIMPROVING DIET
vLIFE STYLE MODIFICATIONS
v REGULAR EXERCISE
vSMOKING, ALCOHILISM CESSATION
vSTRESS REDUCTION
v WEIGHT CONTROL
v BEHAVIOR CHANGE
? When diet changes fail.
? Hypolipidemic drugs will
reduce serum Cholesterol and
Triacylglycerol.
Therapeutic Principle:
Lowering Blood Cholesterols
Inhibition of Cholesterol
biosynthesis
Inhibition of Cholesterol
uptake from GIT
Inhibition of Bile acid reuptake
LDL apheresis (Taking away)
Inhibition of Cholesterol Ester
Transfer Protein (CETP) to some
extent increases HDL levels.
? Cholestyramine Resins:
Block reabsorption of bile acids.
? Sitosterols:
acts by blocking the absorption of
Cholesterol from the
gastrointestinal tract.
? Mevocore or Lovastatin:
inhibitors of HMG-CoA Reductase
Lipoprotein Metabolism
Role Of Lipoproteins
In
Health And Disease
Transportation Of Lipids
Lipoprotein Metabolism
And
Related Disorders
What are Lipoproteins ?
vLipid compounds: Relatively
insoluble in water
vTherefore, they are transported
in plasma and Lymph (aqueous
phase) as Lipoproteins
?Lipoproteins are complex
macromolecules
?Biosynthesized by
aggregation of Lipids and
Proteins.
? Lipoproteins are compound
Lipids/Conjugated Proteins.
? Lipoproteins acquire charge and
made soluble in aqueous phase.
Structure Of Lipoproteins
?Non polar Lipids are at
center
?Polar Lipids and
Apoproteins are present
at periphery.
Hydrophobic lipids
Amphiphilic lipids
Structure Of Lipoprotein
Structure of lipoprotein
Hydrophobic lipids (TAG, CE) in the core
Amphiphilic lipids (C, PL) and proteins on the
surface
Plasma Lipoproteins (Structure)
? Non-covalent
assemblies of lipids
and proteins
? LP core
? Triglycerides
? Cholesterol esters
? LP surface
? Phospholipids
? Proteins
Function as transport vehicles
? Cholesterol
for triacylglycerols and
cholesterol in the blood
Function/Role Of Lipoproteins
?Lipoproteins function
as transport vehicles
?For transportation of
insoluble form of
Lipids in blood plasma.
? Lipoproteins deliver the
lipid components
(Cholesterol and TAG etc.)
from one tissues to
various tissues for their
utilization.
? Various Lipoproteins formed within
the body cells
? Serves in transportation of
exogenous (Dietary Source) and
endogenous (Those Lipids
biosynthesized)lipids
? From one organ to another
through aqueous phase of Lymph
and blood.
Lipoproteins Role Facilitate
?Substrates for Energy Metabolism (TAG)
?Provide Essential components for cells
(PL, C)
?Precursors for Hormones (Cholesterol)
?Carries Lipid soluble Vitamins
?Precursors for Bile acids and Bile salts (C)
Types Of Lipoproteins
? There are different types of Lipoproteins
depending upon:
I. Site of Lipoprotein Biosynthesis
I . Lipid Contents
I I. Apoprotein Contents and Type
IV. Diameter /Size
V. Transport Destination
VI. Ultracentrifugation
VI . Electrophoretic Pattern
Lipoproteins
Site Of
Destination
Major
Biochemical
Synthesis
Lipids
Functions
Chylomicrons Intestine Liver
Exogenous
Deliver lipids of
Triacylglycerol
dietary origin to
Liver and
Adiposecytes
VLDLs
Liver
Extra Hepatic
Endogenous
Deliver
Tissues
Triacylglycerol
endogenously
produced Lipids
to
Extrahepatocytes
LDLs
Intravascular Extra hepatic
Cholesterol
Deliver
removal of
Tissues
endogenously
Triacylglycerol
produced
from VLDL
cholesterol to
Extrahepatocytes
HDLs
Liver and
Liver and steroid-
Phospholipid
Remove and
intestine
hormone-
Cholesterol
degrade
producing glands
Cholesterol.
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
Composition (%)
Proteins 2 10 20 40
Lipids 98 90 80 60
Lipid composition (%)
TAG 88 55 12 12
CE+C 4 24 59 40
PL 8 20 28 47
Free fatty acid - 1 1 1
Chylomicrons
Very low density
Lipoprotein (VLDL)
Low density
Lipoprotein (LDL)
High density
Lipoprotein (HDL)
Lipoproteins
Lipoprotein Nomenclature, Composition
and separation
CM
VLDL
LDL
HDL
Major ApoB 48 ApoB 100 ApoB 100 ApoA-I
Protein
Major TAG
TAG CE
PL
and CE
Lipid
Ultracentrifugation
of
Lipoproteins
Lipoprotein
Particles with distinct densities
1.Electrophoresis
2. Ultra centrifugation method
method:
CM (chylomicron )
CM (chylomicron)
Slow
very low density lipoprotein (
Slow
VLDL)
-Lipoprotein
low density lipoprotein ( LDL)
pre -Lipoprotein
high density lipoprotein (HDL)
Fast
High
- Lipoprotein
Lipoprotein Electrophoresis
Plasma Lipoproteins
For Triacylglycerol Transport (TAG-rich):
- Chylomicrons: TAG of dietary origin
- VLDL:TAG of Endogenous (hepatic)
synthesis
For Cholesterol transport (cholesterol-rich):
LDL: Mainly Free Cholesterol
HDL: Mainly esterified Cholesterol
Important Enzymes and
Proteins
Involved in
Lipoprotein Metabolism
Lipoprotein Lipase
OR
A Clearing Factor
Lipoprotein Lipase (LPL)
LPL is located in the
?
endothelial lining of
blood vessels.
Lipoprotein Lipase (LPL)
? LPL is an extracel ular enzyme,
anchored by Heparan sulfate to the
capil ary wal s of most tissues
? It is predominantly present in
Adipose tissue, Cardiac & Skeletal
muscle
? LPL requires Apo C-II for its activation
? LPL degrades TAG into Glycerol and free
fatty acids by its activity.
? Insulin stimulates its synthesis and
transfer to the luminal surface of the
capil ary.
Lipoprotein Lipases
? Lipoprotein Lipases in capil aries of
adipose and muscle tissues hydrolyze
TAG in VLDLs.
? VLDLs become IDLs
? IDLs looses more TAG and become LDLs.
? LDLs are less in TAG and rich in
Cholesterol and Cholesterol-esters.
? Lipoprotein Lipase act upon TAG
of Lipoproteins and hydrolyze it
? LPL Transforms the ?
?Chylomicron to Chylomicron
remnant
?VLDL to LDL
? LPL clear the circulating
Lipoproteins from blood
hence it is termed as
Clearing Factor.
? Type I Hypolipoproteinemia
? This is termed as Familial
Lipoprotein Lipase deficiency
? Caused due to:
?LPL defect
?Apo C-I is defect
? LPL Hydrolyzes Triacylglycerol (TAG)
in the core of CM and VLDL to free
Fatty acids and Glycerol.
? The released free fatty acids and
Glycerol
? Then enter into the tissue, mainly
adipose, heart, and muscle (80%),
while about 20% goes indirectly to the
Liver.
LPL Mediated Fatty Acid Uptake
Hepatic Lipase (HL)
? HL is bound to the surface of Liver
cells
? Hydrolyzes TAG to free fatty acids
and Glycerol
?HL is concerned with TAG hydrolysis
in Chylomicron remnants and HDL
coming to Liver.
LCAT
(Lecithin Cholesterol Acyltransferase)
Formation of Cholesterol Esters in Lipoproteins
? LCAT is associated with HDL
Lipoprotein.
? LCAT esterifies the Cholesterol
and to HDL.
CETP
(Cholesteryl Ester Transfer Protein)
Cholesterol Ester Transfer Protein
CETP
? CETP is also termed as plasma
lipid transfer protein.
? CETP exchanges Lipids from
one Lipoprotein to another.
CETP Activity
? CETP is a Plasma Protein that
facilitates the transport of
? Cholesteryl Esters and
Triacylglycerol between the
Lipoproteins.
?By CETP activity
Cholesteryl Ester May be
transferred from HDL to:
? VLDL
? IDL
? LDL
? CETP transfers TAG from VLDL or LDL
to HDL
? In exchange of Cholesteryl Esters
from HDL to VLDL.
? HDL either transfers Cholesterol &
Cholesterol esters.
? To Liver by means of CETP
CETP by its activity
Transforms HDL
HDL 3 to HDL 2
Sub fractions Of HDL
HDL2 and HDL3
?Prior to CETP activity HDL is
smaller particles termed as
HDL3
? Post CETP activity HDL3
become larger TAG rich and
termed as HDL2
?HDL 3 is Cholesteryl
Ester rich biomolecule.
?HDL 2 is TAG and CE
containing.
? The receptors present on
Hepatocytes are for HDL 2.
? HDL 2 is internalized in the
hepatocytes and get
metabolized.
Significance Of CETP Activity
? Significance of CETP activity is to
transfer
? The valuable functional compound
Cholesterol from HDL to VLDL and get
transported to extrahepatocytes when
it is required for its use.
? Hence CETP activity is induced when
there is need of Cholesterol to
Extrahepatocytes.
?CETP activity reduces the
content of Cholesteryl
Ester of HDL.
? Low CE content of HDL after
CETP activity
? Increases the HDL associated
LCAT activity.
Inhibition Of CETP Activity
Causes High HDL levels In
Blood Circulation
? Inhibition of CETP will not transfer the HDL
Cholesteryl Ester to VLDL, for use in extra
hepatocytes.
? Not modify HDL3 to HDL2
? No internalization of HDL3 by hepatocytes.
? This may elevate the levels of HDL3 in blood.
? Defective Scavenging role of HDL
? This leading to its bad consequences of
Atherosclerosis.
? Inhibition of CETP increases HDL3
levels.
? But highly reduced CETP activity
accelerates very high HDL3 levels.
? This abnormal high levels of HDL3
evidenced showing development of
Atherosclerosis and Coronary Heart
Diseases.
?Recent Studies have
evidenced
?The CETP inhibiting drugs
?Elevates the levels of HDL3
and
?Increases the mortality
rate.
Apolipoproteins
Functions of
Apolipoproteins
? Apoproteins are protein parts of
Lipoprotein structure
? Apoproteins act as structural
components of Lipoproteins
?Apoproteins are polar moieties
which impart solubility to
Lipoprotein structure.
? Apoproteins
? Recognizes the Lipoprotein
receptors on cell membrane
surface as ligand.
? Which further facilitates the
uptake of LP by specific
tissues.
Apoproteins Activate /Inhibit
Enzymes Involved
in Lipoprotein metabolism.
v Apo A I: Activator LCAT
v Apo C-I : Activator of LCAT
v Apo A-IV: Activator of LCAT
? Apo C-II: Activator of LPL
? Apo C-III: Inhibitor of LPL
? Apo AII: Inhibitor of Hepatic Lipase (HL)
? Chylomicrons contain ApoB-48.
? VLDLs, IDLs and LDLs has ApoB-100.
HDL transfers
Apo E & Apo CII
to
Chylomicrons & VLDL
Chylomicron
Metabolism
Metabolism of Chylomicrons
Surface Monolayer
Phospholipids
Free Cholesterol
Protein
Hydrophobic Core
Triglyceride
Cholesteryl Esters
Chylomicrons
? Assembled in intestinal mucosal
cel s
? Has lowest density
? It has largest size
? Highest % of lipids and lowest %
proteins
? Highest concentration of
Triacylglycerol (dietary origin)
? Chylomicrons carry dietary lipids
from intestine to Liver
? Responsible for physiological milky
appearance of plasma (up to 2
hours after meal)
? Chylomicron is a type of
Lipoprotein
? Formed in the intestinal
mucosal cells
? Due to aggregation of
dietary digested and
absorbed Lipids.
? The Chylomicrons has 99%
Lipids and 1% Proteins
? The predominant Lipid present
in Chylomicrons is
Triacylglycerol (TAG) of dietary
origin.
? The Apoprotein of Chylomicron is
B48
? Significant role of Chylomicron is
to transport dietary Lipids from
intestinal mucosal cell to Liver via
Lymph and Blood.
? Chylomicrons formed in
intestinal mucosal cells are
? First released in lymphatic
system
? Which then enters systemic
blood circulation via thoracic
duct.
? Chylomicrons in blood circulation are not
moved inertly
? But receives Apo C I and Apo E from the
circulating HDL and gets mature.
? Apo C I then stimulates the enzyme
Lipoprotein Lipase present in endothelial
lining of blood vessels of Adipose tissue
and Cardiac tissue.
? The stimulated Lipoprotein Lipase acts
upon TAG of Chylomicrons ,
? Hydrolyze it into free fatty acids and
Glycerol ,which then enters to
adjacent adiposecytes.
? Entered Free fatty acids TAG and
stored as reserve food material.
? The circulating Chylomicrons
are continuously acted upon by
Lipoprotein Lipase
? Most of the TAG is removed
from it and transformed to
Chylomicron remnant till they
reach Liver.
? The Liver has receptors for
Chylomicron remnant.
? Chylomicron remnant linked to
receptors of hepatocytes are
internalized and metabolized in
Liver.
? Chylomicrons transport dietary TAG
and Cholesterol from the intestine to
the peripheral tissues
? Lipoprotein lipase (LPL) is
activated by Apo C-II
? After most of the TG is removed,
Chylomicrons become
Chylomicron remnants. During
the process, CM give ApoC and
ApoA back to HDL
?CM remnants bind to specific
receptors on the surface of liver
cells through apo E and then the
complex is Endocytosed.
?Remnant receptor or ApoE
receptor or LRP (LDL receptor-
related protein)
? Chylomicron remnants deliver
dietary cholesterol and some
cellular cholesterol (via HDL)
to the liver.
? Half life of CM is short, less
than 1 hour.
Chylomicrons
Nascent Chylomicron are formed in the intestinal and
consists of rich in dietary TG + minimal amount of
dietary cholesterol + Apo (B-48)
Mature Chylomicron after Nascent chylomicron
passage to blood, addition of Apo C II and Apo E from
HDL
Lipoprotein lipase hydrolyzes TAG present in
Chylomicrons
Chylomicron remnant taken up by the liver through
endocytosis.
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;
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.
Metabolism of VLDL and LDL
Formation and Fate Of VLDL
? The Lipoprotein Very Low
Density Lipoprotein (VLDL)
? Biosynthesized in
Hepatocytes and Intestinal
Mucosal Cells.
?The endogenously
biosynthesized Lipids are
aggregated
?Along with Apoprotein B-
100 to form VLDL.
? VLDL predominantly
contains Triacylglycerol of
endogenous origin.
Role Of VLDL
? VLDL facilitates in mobilizing out the
endogenously synthesized Lipids in
Hepatocytes and Intestinal mucosal cells.
? VLDL transports endogenous Lipids
from Liver to Extra Hepatocytes via
blood.
?Nascent VLDL accepts Apo
CII and Apo E from HDL
?This modify it to mature
VLDLs in blood.
? Nascent VLDL: contains Apo B-100
? Mature VLDL: Apo B-100 plus
Apo C-II and Apo E
(from HDL)
? Apo C-I is required for activation of
Lipoprotein lipase
? Lipoprotein lipase is required to
degrade VLDL TAG into Glycerol and
fatty acids
?Circulating VLDL on
action by Lipoprotein
Lipase hydrolyzes most
of its TAG.
?VLDL gets modified to
IDL and LDL.
? Thus intermediate product of
IDL and end product LDL are
formed from VLDL
? In blood circulation by action
of LPL on VLDL and removal of
TAG from it.
Normal VLDL Metabolism
Prevents the person
to
Suffer from Fatty Liver
? VLDL help in mobilizing out the
endogenously biosynthesized Lipids
of Hepatocytes.
? Normal Formation and mobilization
of VLDL prevents from accumulation
of excess Fat in the Liver and
develop Fatty Liver.
Modifications of Circulating VLDLs
VLDL IDL (returns Apo E to HDL) LDL
VLDL Metabolism
Dietary Carbohydrate Increases
VLDL Production
Plasma
Triglyceride
Dietary
(VLDL)
Carbohydrate
VLDL Remnants
IDL and LDL
? LDL results from loss of TAG in
VLDL
? LDL contains relatively more
Cholesterol esters
? LDL looses all Apo lipoproteins
except ApoB100.
Very Low Density Lipoprotein (VLDL)
Nascent VLDLare formed in the liver and consists of
endogenous TG + 17 % cholesterol + Apo (B-100)
Mature VLDL after Nascent VLDL passage to
blood, addition of ApoC II, ApoE and cholesterol
esters from HDL
Lipoprotein lipase (LPL) hydrolyzes TAG present
in VLDL
VLDL remnant containing less of TG and more of
cholesterol and taken up by the liver through
endocytosis.
Apo C removed and returns to HDL
LDL Metabolism
Most core lipid in LDL is Cholesterol ester.
ApoB100 is only Apolipoprotein in the surface.
Formation and Fate Of LDL
? Low Density Lipoprotein (LDL) is a
Lipoprotein formed from VLDL in
blood circulation.
? VLDL in blood circulation
receives Apo CII and Apo E from
the circulating HDL.
? Apo CI then stimulates the
Lipoprotein Lipase enzyme
present in the endothelial lining
of blood vessels.
? Lipoprotein Lipase then acts upon
TAG present in VLDL ,hydrolyze it
to Glycerol and free fatty acids
?LDL is the modified
form of VLDL formed
in blood circulation.
?LDL is remnant of
VLDL
?LDL is mostly associated
with Cholesterol and
Phospholipids with
minimal TAG
?Of endogenous origin
mobilized out from Liver.
? The major Apoproteins of LDL
is Apo B100
? Same as VLDL since LDL is
derived from VLDL
? Function of LDL is to transport
endogenously biosynthesized
Cholesterol from Liver to the
peripheral /extrahepatic tissues.
LDL Receptor
?LDL receptor is also named
as ApoB100/ApoE
receptors
?Since ApoB-100 of LDL
binds to LDL receptor.
?The complexes of LDL and
receptor are taken into the
cells by endocytosis,
?Where LDL is degraded but
the receptors are recycled
? LDL receptors are found on cel
surface of many cel types of
extrahepatocytes.
? LDL is internalized by the tissues
when LDL get fixed to the LDL
receptors.
? LDL receptor mediates
delivery of Cholesterol
? By inducing endocytosis
and fusion with Lysosomes.
? Lysosomal lipases and
proteases degrade the LDL.
? Cholesterol then incorporates
into cell membranes or is
stored as cholesterol-esters of
extrahepatocytes.
LDL Receptor
LDL Cholesterol levels
are
positively related to risk
of Cardiovascular
Disease.
?LDL values within
normal range is an
indication of healthy
status.
?But the high LDL levels
are abnormal .
? The Cholesterol associated to
this high levels of LDL
molecules increases the risk of
Atherosclerosis and CVD.
? Hence this LDL associated
Cholesterol is termed as "bad
Cholesterol"
Defect/Absence of
LDL Receptors
Leads to Accumulation of LDL
in Blood Circulation
Causing
Hypercholesteremia
and
Atherosclerosis
? Defect in LDL receptors on tissues
impairs LDL metabolism.
? Decreases LDL internalization
within the tissues.
? Increases abnormal levels of LDL in
blood (< 130 mg%).
? Increased LDL levels in
blood circulation due to
defect in LDL receptors is
termed as Type I a
Hyperlipoproteinemia.
? The major form of Lipid associated with LDL
is Cholesterol .
? Hence increased LDL levels is characterized
by Hypercholesterolemia.
? The Cholesterol associated with elevated
levels of LDL (more than its normal range) is
termed as bad Cholesterol,
? Since it increases the risk of Atherosclerosis
and its complications .
? Persons lacking the LDL
receptor suffer from Familial
Hypercholesteremia
? Due to result of a mutation in
a single autosomal gene
? Total plasma cholesterol and
LDL levels are elevated.
?Cholesterol Levels of:
?Healthy person = < 200 mg/dl
?Heterozygous individuals = 300 mg/dl
?Homozygous individuals = 680 mg/dl
High LDL levels can lead to
Cardiovascular Disease
Most Homozygous individuals
die of cardiovascular disease
in childhood
? LDL can be oxidized to form
oxidized LDL
? Oxidized LDL is taken up by
immune cells cal ed
macrophages.
? Macrophages become
engorged to form foam cells.
? Foam cel s become trapped in
the wal s of blood vessels and
contribute to the formation of
atherosclerotic plaques.
? Causes narrowing of the
arteries which can lead to
MI/heart attacks.
Familial hypercholesterolemia is due to a gene
defect in the LDL receptor
? Michael Palmer 2014
Role Of HDL
Reverse Transport Of
Cholesterol
?HDL is a high density
Lipoprotein.
?Nascent HDL is
biosynthesized in Liver.
? HDL is the Lipoprotein, with highest
density.
? Since it is associated with 40-50% of
Apoproteins.
? The Apoproteins of HDL are Apo A I,
Apo A I , Apo C I,C I , Apo D and Apo E.
? HDL serves as a reservoir of
Apoprotein during its circulation.
? HDL gives it Apo CII and Apo E to
circulating nascent Chylomicrons
and VLDL .
? Nascent HDL of discoid shaped
(Empty Bag) biosynthesized in
Liver
? It is released in the blood
circulation for scavenging action.
The HDL has Scavenging Action
It serves as a
Scavenger For
Unwanted Body Lipids
? The Enzyme Lecithin Cholesterol Acyl
Transferase (LCAT) is associated with HDL
metabolism.
? Apo A I,A IV and CI stimulates the LCAT
activity of HDL.
? LCAT by its activity help in esterification of
free Cholesterol to Esterified
Cholesterol/Cholesterol Ester.
? HDL by its scavenging action collects the extra
non functional Cholesterol lying in blood
vessels and peripheral tissues.
? HDL esterifies Choleserol by its LCAT activity
and to HDL bag.
? The nascent HDL bags changes to spherical
shape .
? HDL is more associated with Phospholipids
and Cholesterol.
? The receptors for HDL are
present on Liver cells.
? HDL transports the excess,
unused Lipids from extra
hepatic tissues back to Liver for
its metabolism and excretion.
? The role of HDL is opposite to LDL.
? HDL transports Cholesterol From
extra hepatic tissues back to Liver.
? Thus the role of HDL is termed as
reverse transport of Cholesterol.
? Normal serum HDL levels are 30-60
mg%.
? The efficient activity of HDL is good
to the body
? As it prevents risk of Atherosclerosis
and their complications.
Reverse Cholesterol Transport (RCT)
High Density Lipoproteins (HDL ? Good)
? CETP by its activity modifies HDL 3
to HDL 2.
? HDL2 is then get internalized in
Hepatocytes for its final use.
? Cholesterol Ester carried by HDL to
hepatocytes is degraded to Bile
acids and Bile salts and get excreted
out.
Fate of HDL
HDL 2 binds SR-B1 receptor on Hepatocytes
Transfers Cholesterol &
Cholesterol ester to cell
Depleted HDL dissociates
& re-enters circulation
? HDL can bind to specific
hepatic receptors SR-B1
? But primary HDL clearance
occurs through uptake by
scavenger receptor SR-B1.
? SR-B1 can be upregulated in cells
when Cholesterol levels are low in
hepatic cells.
? SR-B1 is down regulated when
cholesterol levels are high in cells.
? Defect in low HDL synthesis in Liver
lowers the HDL activity and increases
the risk of Atherosclerosis.
? Defect in HDL receptors on Liver may
abnormally increase the HDL levels in
blood circulation and also increases the
risk of Atherosclerosis.
The Lecithin-Cholesterol Acyltransferase (LCAT)
reaction
Cholesterol esters can be stored inside lipoprotein
particles
HDL Interactions
with Other Particles
Tangier Disease: Disruption of Cholesterol
Transfer to HDL
? Michael Palmer 2014
HDL and Reverse Cholesterol Transport
Tangier Disease
LDL-R
LDL-R
50% of HDL C may
Return to the liver
On LDL via CETP
LDL/HDL Ratio and Cardiovascular Disease
? LDL/HDL ratios are used as a
diagnostic tool for signs of
Cardiovascular disease
? A good LDL/HDL ratio is 3.5
?LDL above normal range =
"Bad Cholesterol"
?HDL within normal range =
"Good Cholesterol"
-HDL above normal range =
"Bad Cholesterol"
? Protective role of HDL is not very
clear.
?An esterase that breaks down
oxidized lipids is associated with
HDL.
?It is possible (but not proven) that
this enzyme helps to destroy
oxidized LDL
Lipoproteins Facilitate Lipid
Transport
Normal
Lipoprotein Metabolism
Normal LP Metabolism
? Maintains Normal levels of Lipoproteins
in the blood circulation by:
?Normal Formation of LP by specific tissues
?Normal Transformation and Transport of
LP in blood
?Normal Uptake of LP by specific tissues
? Normal Lipoprotein
Metabolism Reduces the risk
of:
?Atherosclerosis
?Myocardial Infarction
?Stroke
Lipoprotein Population Distributions
? Serum Lipoprotein
concentrations differ between
adult men and women.
? Primarily as a result of
differences in sex hormone
levels.
? Women having, on average, higher HDL
cholesterol levels and lower total
Cholesterol and TAG levels than men.
? The difference in total cholesterol,
however, disappears in post
menopause as Estrogen decreases and
use of Cholesterol is reduced.
Lipid Associated Disorders
OR
Lipid Related Clinical Problems
? DysLipoproteinemias/Dyslipidemias
(Hypo and Hyperlipoproteinemias)
? Fatty Liver
?Atherosclerosis
?Coronary Heart Diseases
Causes of Lipid Associated Disorders
? Diseases associated with abnormal lipid
concentrations can be caused:
?Nutritional Imbalances
?Environmental Factors
?Lifestyle Patterns
?Genetic abnormalities
?Develop secondarily, as a
consequence of other diseases.
Disorders Of Lipoproteins
Dyslipoproteinemias/ Dyslipidemias
Hyperlipoproteinemias
And
Hypolipoproteinemias
Abnormal LP Metabolism
? Abnormal Synthesis of LP by specific
tissues
? Abnormal Transport of LP in blood
? Abnormal Uptake by specific tissues
? Leads to abnormal levels of Lipoproteins
in the blood circulation
? Thus conditions and factors
which affects the
Lipoprotein synthesis,
transport and uptake
? May lead to Lipoprotein
disorders/Dyslipidemias.
Dyslipidemias
? Dyslipidemias are due to Defect in
Lipoprotein metabolism
? Include both the excess and
deficiency of Lipoproteins.
? Dyslipidemia can manifest as the
elevation of plasma Cholesterol,
Triacylglycerol, or both.
? It can also be manifested by:
?The elevation of LDL Cholesterol
?The abnormal decrease/increase
of HDL Cholesterol in the blood.
Causes Of Dyslipidemias/
DysLipoproteinemias
? Dyslipedimias states are generally
caused by impaired Lipoprotein :
?Biosynthesis (Increased)
?Transformation and Transport
(Improper )
?Uptake and Utilization (Decreased)
Dyslipidemias/Dyslipoproteinemias
? Dyslipidemias can be subdivided into two
major categories
1. Hyperlipoproteinemias
? Hypercholesterolemia
? Hypertriglyceridemia
? Combined Hyperlipoproteinemia
2. Hypolipoproteinemias
Types Of Lipoprotein Disorders
Hyperlipoproteinemias
? Hyperlipoproteinemia are
abnormal conditions
? With increased levels of
circulating Lipoproteins in
the blood.
Causes of Hyperlipoproteinemia
? Increased formation of Lipoprotein
? Reduced clearance of LP from circulation
? Factors Causing These
? 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
? Defect in Receptors for LP
? Use of drugs that perturb LP formation or
catabolism
Types of
Hyperlipoproteinemias
Fredrickson Classification
of
Hyperlipoproteinemia
Type I
Lipoprotein Lipase Deficiency
Increased Chylomicrons and
Hyperlipoproteinemia VLDL
Hypertriglyceridemia
Type II a Defect in LDL Receptors
Increased LDL levels in blood
Hyperlipoproteinemia Hyperbetalipoproteinemia
Hypercholesterolemia
Type II b Increased production of Apo B
Increased production of
Hyperlipoproteinemia VLDL and impaired LDL
catabolism Increased VLDL and
LDL
Type I I
Defect in ApoE
Familial Dysbeta Broad Beta Disease
Lipoproteinemias Increased IDL
Type IV
Impaired VLDL metabolism.
Increased VLDL
Hyper-pre-b-
Lipoproteinemia
Due to acquired conditions viz
q Obesity
q Alcoholism
q Diabetes mel itus
Increased VLDL and
Chylomicrons
Due to acquired
Type V conditions viz
q Obesity
Combined
q Alcoholism
Hyperlipoproteinemia
q Diabetes mel itus
Conditions Of Hyperlipoproteinemias
? Increased endogenous/exogenous
availability of Lipids
? Increased/Defective Apoprotein
synthesis
? Decreased Lipoprotein Lipase activity
? Defective receptors on specific tissues
Deficiency Of Lipoprotein Lipase
Leads To
Familial Type I Hyperlipoproteinemia
? Defect in Lipoprotein Lipase activity
? Does not clear the circulating
Chylomicrons and VLDL;
? Increases the levels of circulating
Chylomicrons and VLDL
? Associated Hypertriglyceridemia
? This is termed as Familial Type I
Hyperlipoproteinemia.
Type I Hyperlipoproteinemias
? Shows a dramatic accumulation (1000
mg/dl) of Chylomicrons and VLDL in
plasma
? Usual y associated with
acute abdomen due to
acute pancreatitis
? plasma TAG even in the
fasted state
Type I I Hyperlipoproteinemia
? Familial dysbetalipoproteinemia
? Due to Apo E deficiency
? Associated with
Hypercholesterolemia &
premature Atherosclerosis
Hypolipoproteinemias
Hypolipoproteinemias
? Hypolipoproteinemias are
abnormal conditions
? With decreased levels of
circulating Lipoproteins in
the blood.
Conditions Of Hypolipoproteinemias
? Decreased synthesis of
Lipoproteins
? Deficiency of Lipotropic factors
required for Lipoprotein
biosynthesis.
Types Of Hypolipoproteinemias
Familial Hypobetalipoproteinemia
?Impairment in the
synthesis of Apo B
?Characterized with low
LDL levels.
Abeta Lipoproteinemia
? Rare disorder
? No synthesis of Apo B (Total
Absence)
? Absence of LDL (Beta Lipoprotein) in
blood circulation
? Defect in TAG-transfer protein
? Accumulation of TAG in liver
Familial Alpha Lipoprotein Deficiency
Tangiers Disease
? Absence of HDL (Alpha Lipoprotein)
in blood
? Affects severely Reverse transport
of Cholesterol
? Hypercholesterolemia
? Increased risk of Atherosclerosis and
its Complications.
Classification Of
Dyslipidemias
Based On
Number Of Gene Involvement
Primary Hyperlipoproteinemia
?Monogenic defect
?Polygenic Defect
Monogenic Disorders
vFamilial Hypercholesterolemia
vHomozygous or Heterozygous
vDefect: inactive LDL receptor
vFamilial Lipoprotein Lipase deficiency
vDefect: inactive lipoprotein lipase
vFamilial combined Hyperlipidemia
vDefect: Unknown
Polygenic/Multifactorial
? These are commonly
encountered
vHypercholesterolemia
vHypertriglyceridemia
Secondary Hyperlipidemias
?Alcoholism
?Diabetes mellitus
?Uremia
?Drugs; b blockers, oral contraceptives,
thiazide diuretics
?Diseases: Hypothyroidism, Nephrotic
syndrome, Obstructive liver disease
Combined Hyperlipoproteinemia
? Presence of elevated levels of both serum
Total Cholesterol and Triacylglycerols.
? Genetic form of this condition
?Familial Combined Hyperlipoproteinemia
(FCH)
?Type V Hyperlipoproteinemia
? An accumulation of Cholesterol-rich VLDL
and Chylomicron remnants as a result of
defective catabolism of those particles
1389
Diagnosis And Therapeutic
Strategy Of Dyslipidemias
A. Identify patients at risk
1. Routine screening of Serum Lipid
profile
2. Assessment of contributing risk factors
B. Non-Pharmacologic therapy
1. Diet modification
2. Lifestyle modification
C. Pharmacologic therapy
? Lipids and lipoproteins are
important indicators of CHD risk,
? This is the major reason for their
measurement in research, as well
as in clinical practice.
Estimation Of Lipid Profile
? Serum Triacylglycerol
? Serum Total Cholesterol
? Serum VLDL
? Serum LDL Cholesterol
? Serum HDL Cholesterol
Hypertriglyceridemia
? Serum Triacylglycerol
? Borderline = 150-200 mg/ dl
? High 200-500 mg/dl
? Very High > 500 mg/dl
? Familial Hypertriglyceridemia
? Genetic
? Secondary Hypertriglyceridemia
? Hormonal imbalances
? Imbalance between synthesis and clearance of VLDL
1394
Hypertriglyceridemia
? Generally caused by deficiency of LPL or
LPL cofactor.
? LPL hydrolyzes TAG in Chylomicrons and
VLDL
? Deficiency of LPL prevents processing and
clearing of Lipoproteins.
? Elevated even with fasting condition.
1395
Hypercholesterolemia
? Familial Hypercholesterolemia (FH)
?Homozygous rare 1/million
?Total cholesterol 800-1000 mg/dl
?Heart attack as early as teenage years
?Heterozygous cholesterols 300-600
mg/dl
?Heart attacks 20-50 years
Hypercholesterolemia
? Familial hypercholesterolemia (FH)
?Primarily LDL elevations
?Synthesis is normal but decrease or lack
LDL receptors
?Therefore LDL builds-up in serum
?Since cells cannot acquire from LDL
increase internal synthesis
Lipid Profile and Lipoprotein Analyses
LDL Methods
? Friedewald Calculation
? VLDL is estimated as TAG/5
LDL = Total Cholesterol ? HDL ? TAG/5
Lipoprotein Assay Methods
? Separate Lipoprotein Fractions By:
? Electrophoresis ? Agarose or Polyacrylamide
? Chromatographic
? Precipitation
? Ultracentrifugation
? Immunochemical
Serum Triglycerides
Normal
? Less than 150 mg/dL
Borderline High
? 150-199 mg/dL
High
? 200-499 mg/dL
Very High
? 500+ mg/dL
Serum Total Cholesterol
Normal
?Less than 200 mg/dL
Borderline High
?200-239 mg/dL
High
?240 mg/dL or higher
HDL Cholesterol
Optimal:
?60+ mg/dL for both males and females
At Risk for Heart Disease:
?Women: less than 50 mg/dL
?Men: less than 40 mg/dL
LDL Cholesterol
Optimal
? Less than 100 mg/dL
Near or above Optimal
? 100-129 mg/dL
Borderline High
?130-159 mg/dL
High
?160-189 mg/dL
Very High
? 190+ mg/dL
Consequences Of
Dyslipoprotein Metabolism
?Fatty Liver
?Atherosclerosis and
its Complications
Role Of Liver In Lipid Metabolism
? Liver is the Biochemical Factory of
Human Body.
? Liver plays an important role in
Lipid metabolism.
? Major pathways of Lipid
metabolism are efficiently carried
out in Liver.
Lipid Metabolism
At Liver
In Well Fed Condition
? Liver in well fed condition efficiently carries
out various metabolic pathways of Lipid
Metabolism.
?De Novo biosynthesis of Fatty acids
?Triacylglycerol Biosynthesis
?Cholesterol Biosynthesis
?Phospholipid Biosynthesis
?Glycolipid Biosynthesis
?VLDL Biosynthesis
Lipid Metabolism
At Liver
In Emergency Condition
? Liver in emergency condition carries
following metabolic pathways of
Lipid metabolism efficiently:
?Beta Oxidation of Fatty acids
?Ketogenesis
?Bile Acid and Bile Salt Formation
Fatty Liver
? Though Liver is the predominant
site for Lipid biosynthesis.
? Liver is not the storage organ for
Lipids.
?Normally 3-5% of Lipids are
present in Hepatocytes.
? Endogenously biosynthesized
Lipids in Liver are
? Mobilized out in the form of
VLDL molecule.
? Efficient formation of VLDL
in Liver
? Does not al ow the excess
of Lipids to remain in Liver
tissue.
Fatty Liver/
Fatty Liver Disease/
Hepatosteatosis
What Is Fatty Liver?
? Fatty Liver is an abnormal
condition
? Where there is more than 5% of
Lipids retained in Hepatocytes.
What Is Fatty Liver Disease?
? Fatty Liver disease (FLD), is a reversible
condition of Liver
? Wherein large vacuoles of Lipids
accumulate in Liver cel s
? Via the process of Steatosis (Abnormal
retention of Lipids within a cell)
What Is Steatohepatitis ?
? Progressive inflammation of the
Liver (Hepatitis),
? Due to abnormal accumulation of
Lipids(Steatosis) is termed as
Hepatosteatosis/Steatohepatitis
.
Causes Of Fatty Liver
Clinical Conditions
Leading To Fatty Liver
OR
Risks For Developing Fatty Liver
?Defect in Hepatic
?Biosynthesis of Lipids
?No Mobilization of
Endogenously
biosynthesized Lipids in
Liver
?Accumulates Lipids in Liver
? Increased biosynthesis of Lipids than
the mobilization capacity ,due to
increased Carbohydrates.
? Decreased mobilization of Lipids
from Liver cells due to decreased
VLDL formation.
?Deficiency of Lipotropic
factors affects
?The VLDL formation and
mobilization of Lipids
out of Hepatocytes.
Conditions Leading To Fatty Liver
? Metabolic Syndrome
?Obesity
?Hypertension
?Dyslipidemias
?Diabetes mel itus
? Alcoholism
? Malnutrition
(Deficiency of Lipotropic Factors)
? Wilsons Disease
? Hepatitis A
? Hepatitis C
? Hepatotoxic Drugs : MTX, VA,
Acetaminophen, TC, Tamoxifen,
Nefidepine, Amiodarone, CCl4 etc
Lipotropic Factors and Their Role
Adequate Presence of
Lipotropic factor
Prevents Retention of Lipids
in Liver
There by preventing Fatty Liver.
? Lipotropic Factors are chemical
substances which helps in
formation of Phospholipids.
? This in turn helps in proper
formation and mobilization of
VLDL out from Liver.
Names Of Lipotropic Factors
? Lipotropic Factors are chemicals
involved in biosynthesis of
Phospholipids:
?Choline
?Betaine forms Choline
?Inositol
Amino Acids As Lipotropic Agents
?Glycine
?Serine
?Methionine
Vitamins As Lipotropic Factors
?Vitamin B 12
?Folic Acid
Types Of Fatty Liver
4 Types Of Fatty Liver
? Alcoholic Fatty Liver
? Non Alcoholic Fatty Liver Disease (NAFLD)
? Non Alcoholic Steatohepatitis (NASH)
? Acute Fatty Liver of Pregnancy
Consequences Of Fatty Liver
? Fatty liver is a reversible condition
and usual y goes away on its own.
? Generally Fatty liver often has no
symptoms and
? Does not cause any permanent
damage.
Consequences Of Fatty Liver
? Constant accumulation of
abnormal excess amount of
Lipids in Hepatocytes
? Affects the normal Liver
functions
? Leads to Parenchymal damage
to Liver Tissues
? Causes Liver Cirrhosis.
? Excess of Lipids deposition in Hepatocytes
? Interferes the biochemical functions
? Brings inflammation of Liver (Hepatitis)
? Changes the cytological features
? Damages the cell components
? Causes Liver Fibrosis
? Leads to Liver Cirrhosis
? Liver Carcinoma
Natural History of Fatty Liver Disease
Fatty liver
Steatohepatitis
Steatohepatitis + Fibrosis (First Stage of Scar)
Steatohepatitis + Cirrhosis
Cryptogenic Cirrhosis
When there is repeated damage to
the Liver
Permanent scarring of Hepatocytes
takes place
This is cal ed Liver Cirrhosis
Diagnostic Features
OF
Fatty Liver Disease
Laboratory Abnormalities
In Fatty Liver Disease
? 2 - 4 fold ALT &
? Normal Albumin. PT
AST
? Low ANA + < 1 in 320
? AST: ALT Ratio < 1
? Serum Ferritin
? ALP slight in 1/3
? Iron saturation
? Dyslipidemia - TAG ? AST: ALT Ratio > 1
? FBG and PPBG
if Cirrhosis sets in
? BUN & Creatinine - N
Fatty liver Normal liver
Features Of Normal Arterial Wal
? The lumen of healthy arterial wal is
lined by:
?Confluent layer of Endothelial cel s
Features of Normal Endothelium
Controls Important function Of
Arterial wal
vNormal healthy arterial endothelium,
vRepels cells and inhibits blood clotting.
vHealthy arteries are soft and Elastic.
vNormal Endothelium- Regulates tissue and
organ blood flow.
vThe ability of blood vessels to dilate-
vasodilatation
vThe ability of blood vessels to constrict-
vasoconstriction
Arteriosclerosis
What Is Arteriosclerosis?
? Arteriosclerosis is non-specific term used
to describe hardening and thickening of
the wal of arterioles.
OR
? Arteriosclerosis is a general term
describing any hardening (and loss of
elasticity) of medium or large arteries.
What Is Atherosclerosis?
? The term Atherosclerosis, comes
from the Greek words
?Atheros- meaning "gruel" or
"paste"
?Sclerosis- meaning "hardness".
Atherosclerosis
is a form of
Arteriosclerosis
Terms For Atherosclerosis
? There are many terms associated
to Atherosclerosis including:
vAtheroma
v Fibrous Plaques
v Fibro Fatty Lesions
vAtherosclerotic Plaques
? Atherosclerosis are abnormal
Diseased/defective arteries.
?Arteries becomes hard and non elastic
?Arteries are less or non Functional
?Arteries obstruct the normal blood
flow to cells/tissues/organs.
Atherosclerosis is
Hardening of Blood Vessels
due to formation of
Fibro Inflammatory Fatty Lesions/Plaques
? Atherosclerotic Plaque Results
From Accumulation of :
?Lipids
?Connective tissue
?Inflammatory cells
?Smooth Muscle cells
? In the intima of blood vessels.
Causes Of Atherosclerosis
Risk Factors For Atherosclerosis
? Risk factors which accelerate the
progression of Atherosclerosis
and endothelial dysfunction are:
?Dyslipidemias/Dyslipoproteinemias
?Hypercholesterolemia
?Other Cardiovascular risk factors
Unchangeable Risk factors of Atherosclerosis
? Age
? Genetic Alterations
? Male gender
? Men are at grater risk than are premenopausal
women, because of the protective effects of natural
Estrogens.
? Family history of premature coronary heart disease
? Several genetically determined alterations in
lipoprotein and cholesterol metabolism have been
identified.
Changeable Risk Factors Of
Atherosclerosis
vHyperlipidemias:
vThe presence of Hyperlipidemia is
the strongest risk factor for
atherosclerosis in persons younger
than 45 years of age.
vBoth primary and secondary
hyperlipidemia increase the risk.
Dietary Habits
? Eating a Balanced Diet
? Excess of Refined Sugars
? Excess of Saturated fatty acids
? Use of Trans Fatty acids
Dyslipidemias
? Elevated LDL and Triacylglycerol ?
directly associated with increase
risk
? Increased Serum HDL levels
? Increased LDL and decreased HDL
v Smoking: dose related
vDiabetes mel itus
vMetabolic Syndrome
vIncreasing age and
male sex
vPhysical inactivity
vStressful life style
vHomocysteine is toxic
to endothelial cel s
vC-Reactive Protein
?A Stressful life style:
? Hormonal
Imbalances
?Oxidative Stress
? Improvement of diet and
drugs may regulate the
levels of blood Lipoproteins
and Lipids which may
reduce the risk of
Atherosclerosis and CVDs.
vHypertension
vHigh blood pressure produces
mechanical stress on the vessel
endothelium.
vIt is a major risk factor for
atherosclerosis in al age groups and
may be as important or more
important than hypercholesterolemia
after the age of 45 years.
vBlood Pressure >160 mmHg
increase the risk for MI
?Regulation of Hypertension
may reduce the risk of
Atherosclerosis.
Less Well Established Risk Factors
? There are a number of other less wel -established risk factors for
atherosclerosis, including:
? High Serum Homocysteine Levels
? Homocysteine is derived from the metabolism of dietary
Methionine
? Homocysteine inhibits elements of the anticoagulant cascade
and is associated with endothelial damage.
? Elevated serum C-Reactive Protein
? It may increase the likelihood of thrombus formation;
? Inflammation marker
? Infectious agents
? The presence of some organisms (Chlamydia pneumoniae,
herpesvirus hominis, cytomegalovirus) in atheromatous lesions
has been demonstrated by immunocytochemistry,
? The organisms may play a role in atherosclerotic development
by initiating and enhancing the inflammatory response.
Reduction Of Atherosclerosis Risk
The risk of atherosclerotic event can
be decreased by:
?Normal Carbohydrate diet
?Regular Exercise
?Smoking cessation
?Control of high pressure
?Drugs Statins, Ezetimibe,
?Intake of Antioxidants
Common Arteries Atherosclerozied
?Aorta and its branches
?The Coronary arteries
? Large vessels that
supply the Brain
3 Stages of Atherosclerosis:
1.Initiation and Formation Stage
2.Adaptation Stage
3.Clinical Stage
Pathogenesis Of Atherosclerosis
?Pathogenesis of
Atherosclerosis includes:
? Genetic Factors
? Environmental Factors
The Development of Atherosclerosis
? The key event is ? damage to the
endothelium.
? The damaged Endothelium
becomes more permeable to
Lipoproteins.
? Lipoproteins move below the
endothelial layer (to intima).
? Damaged Endothelium loses its cel -
repel ent quality.
?Inflammatory cel s move into the
vascular wal .
?Further Endothelial injury occurs by
attachment of leukocyte
(lymphocyte and monocyte) and
Platelet adherence
?Smooth muscle cel emigration and
proliferation
?Activated
macrophages
releases free radicals
that oxidizes LDL.
vLipid Engulfment by
Macrophages
vOxidized LDL engulfed by
Macrophages to form Foam cel s
vSubsequent development of an
atherosclerotic plaque with lipid
core
Effects Of Oxidized LDL
? Oxidized LDL is Toxic to the Endothelium:
? Causing Endothelial loss
? Exposure of the subendothelial tissue to blood
components
? Chemotactic effect on lymphocytes and Monocytes
? Chemotactic effect on smooth muscle cells from the
arterial media
? Stimulates production of MG-CSF, Cytokines,
adhesion molecules in the endothelium;
? Inhibits endothelium derived releasing factor
(EDRF), favoring vasospasm;
? Stimulates specific immune system (production of
antibodies against oxidized LDL).
? Activated Macrophages also ingest
oxidized LDL to become foam cells,
? Which are present in all stages of
atherosclerotic plaque formation.
? Lipids released from necrotic foam
cells accumulate to form the lipid
core of unstable plaques/Fatty
streaks.
?Endothelial disruption
leads :
?Platelet adhesion and
aggregation
?Fibrin deposition
? Platelets and activated
macrophages release various
factors that are thought to
promote growth factors
? This modulate the proliferation
of smooth muscle cells and
deposition of extracel ular
matrix in the lesions: Elastin,
Col agen, Proteoglycans.
? Thus Connective tissue synthesis
and Calcium fixation
determinates stiffness of blood
vessels.
? Which causes further ulceration
of Atheromatous plaque.
Arteriosclerosis
Summary Of Pathogenesis Of
Atherosclerosis
? Accumulation of Lipids in vessel wal
? Source: Plasma Lipoproteins
? Most important: Low-density lipoproteins LDL
? LDL transported inside macrophages to vessel
wal s
? Damage to Endothelium
? Adhesion of Macrophages
? Inflammation at the site
?Fatty Streaks
?Foam cells
?Smal Thrombi
?Calcification
? Plaque formation
?Ulceration
?Stiffening and Hardening
of blood vessels
Lesions Associated with
Atherosclerosis
? The lesions associated with
Atherosclerosis are of three types:
?The Fatty streak
?The Fibrous Atheromatous plaque
?Complicated Lesion
? The latter two are responsible for
the clinical y significant
manifestations of the disease.
? The more advanced complicated
lesions are characterized by:
?Hemorrhage
?Ulceration
?Scar tissue deposits
? As a result of all pathogenic
mechanism
? Atherosclerosis can be defined
as vicious inflammatory process.
Modern Theory of Atherosclerosis
? Multifactor Theory:
?Structural and functional injury of vascular
endothelium
?The role of lipoproteins in initiation and
progression of lesions;
?Response to injury of immune cel s and
smooth muscle cel s
?The role of growth factors and cytokines in
inflammation
?The role of repeated thrombosis in lesions
progression.
Consequences Of Atherosclerosis
OR
Effects/Complications
Of Atherosclerosis
? Atherosclerosis is a chronic
process
? Atherosclerosis affects almost
al people with variable
severity.
? Atherosclerosis develop over
several decades.
? If Congenital in origin It may
starts as early as infancy and
childhood,
? Progress very slowly during
life.
? Atherosclerosis contributes
to more mortality and
? More serious morbidity than
any other disorder in the
western world.
? Atherosclerosis affects the
intimal lining of endothelium
of
? Large and Medium-sized
elastic and muscular arteries
of body.
?Atherosclerotic plaque
formation
?Narrows the diameter of
blood vessel lumen.
? Atherosclerosis leads to the
narrowing or complete blockage of
arteries /Occlusion by:
?Endothelial Dysfunction
?Lipid deposition
?Inflammatory reaction in the vascular
wal
?Ulcerative Lesions
Atherosclerosis BringgsAlterations Of Arteries
:
? Aneurysm-Excessive localized swelling of
blood vessel
? Stenosis-Abnormal narrowing of vessel
? Occlusion-Closing of blood vessel
? Thrombosis-Local clotting of blood
? Embolism -blockage of vessel by lodging
of blood clot/fat globule
? Fissure-Small tear with bleeding
? Ulceration-Removal of top layer
? Calcification- Accumulation of Calcium
Salts
? Atherosclerosis , can and does, occur
in almost any artery in the body.
? Atherosclerosis of coronary arteries is
very crucial
? This blocks, the blood circulation to
Heart
? Which fails the cardiac muscle to
sustain.
? Thus Atherosclerosis leads to
disease of cardiovascular
system affecting blood vessel
wal .
? Causing Ischemic Heart Disease
which is the leading cause of
death in developed countries.
Biochemical Alterations
In Atherosclerosis
Biochemical Basis Of Atherosclerosis
? 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
? Low Cellular Activity
? Cellular/Tissue/Organ Dysfunction
? Irreversible Damage of cells/tissues/organ/system
Diagnosis Of Atherosclerosis
? Checking Lipid Profile/Lipoproteins
? B.P
? ECG
? Angiography
? EEG
? Color Doppler
? MRI
Management Of Atherosclerosis
? Reducing the risk factors
? Correcting the underlying causes
? Angioplasty
? Other Surgeries
Complications of
Atherosclerosis
? 1. Acute Occlusion:
Thrombosis
Occlusion
Ischemia, Infarction
? 2. Chronic Stenosis:
Chronic ischemia
Atrophy
Eg. Renal atrophy in renal artery stenosis, ischemic
atrophy of skin in DM
? 3. Aneurysm Formation:
Extension to media
Aneurysm
Aneurysmal rupture eg. Abdominal
aortic aneurysm
? 4. Embolism:
Of atherosclerotic plaque or of
thrombi
? Thrombosis is the most
important complication of
Atherosclerosis.
? It is caused by slowing and
turbulence of blood flow in the
region of the plaque and
ulceration of the plaque.
PHYSIOPATHOLOGICAL
CONSEQUENCES OF THE PLAQUE
v Coronary Artery Disease (CAD) : Angina, MI
v Cerebro Vascular Disease (CVD)
v Peripheral Artery Disease (PAD)
v Ischemic Stroke (Brain infarct)
v Secondary Erectile Disorder (ED)
v Chronic Renal Ischemia ( Renal failure)
? Atherosclerosis commonly
leads to:
?Myocardial infarction
?Stroke
?Gangrene of extremities
The Process of Atherogenesis
Progression of CHD
Damage to
endothelium and
invasion of
macrophages
Smooth muscle
migration
Cholesterol
accumulates
around
macrophage and
muscle cel s
Collagen and
elastic fibers
form a matrix
around the
cholesterol,
macrophages
and muscle cel s
Pathogenesis of Coronary Heart Disease (CHD)
Plaque Build up in Artery
Overview of the Artery
The Development of Atherosclerosis
Monocyte Recruitment
LDL
lumen
intima
Plaque Rupture and Thrombosis
Tissue Factor
Platelet Aggregation
Lipid Core
NO Inactivation Due to Oxidative Stress
Sch?chinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055
Sch?chinger V., Zeiher A.M.: Nephrol Dial Transplant (2002): 2055
The Process of Atherogenesis ? an overview
Formation of Atherosclerotic Plaques
lumen
neointima
Lipid Core
Cardio Vascular Disorders (CVD)
Coronary Artery Disease (CAD)
OR
Coronary Heart Disease(CHD)
OR
Ischemic Heart Disease(IHD)
Coronary Heart Disease
? The term Coronary Heart Disease
(CHD) describes Heart disease
caused by impaired coronary
blood flow.
? In most cases, it is caused by
Atherosclerosis of coronary
arteries which supply
Myocardium.
Clinical Manifestations
?The clinical manifestations
of Atherosclerosis depend
on:
?The vessels involved
?The extent of vessel
obstruction
? Atherosclerotic Lesions produce their
effects through:
?Narrowing of the blood vessel and
production of Ischemia;
?Sudden vessel obstruction caused by
Plaque hemorrhage or rupture;
?Thrombosis and formation of emboli
resulting from damage to the vessel
endothelium;
Coronary Artery Diseases Can cause:
?Angina/Chest Pain
?Myocardial Infarction /Heart attack
?Cardiac dysrhythmias
?Conduction defects
?Heart failure
?Sudden death
Myocardial Infarction
Myocardial Infarction
? MI is an irreversible damage
to Myocardium(Heart tissue)
? Acute myocardial infarction
(AMI), also known as a heart
attack
?AMI is caused due to
associated
Atherosclerotic disease
of the coronary arteries.
Risk Factors OF MI
Uncontrollable
Control able
?Sex
?High blood pressure
?High blood cholesterol
?Hereditary
?Smoking
?Race
?Physical activity
?Obesity
?Age
?Diabetes
?Stress and Anger
Screening and Diagnosis
me
mea
a
s
s
u
sh
u
re
ows
r
s
es
fic
eci
s
e
blood
sp
rical
Electro-
Stress
Coronary
ri
a
n
ect
cardiogram
Test
t
S
Angiography
ro
el
i
o
te
c
s o
su
f
p
to hear
ulses
ply
imp
Narrowing in
Diagnosis Of MI
1. Pain
? Severe and Crushing,
? Constricting, Suffocating.
? Usual y is Sub Sternal, radiating to the left
arm, neck, or jaw
? Gastrointestinal Complaints
?Sensation of Epigastric distress
?Nausea and Vomiting
ECG
? Elevation of the ST segment
usually indicates acute myocardial
injury.
? When the ST segment is elevated
without associated Q waves, it is
called a Non?Q-wave Infarction.
Diagnostic Biochemical Markers Of MI
Enzymes and Proteins
? Lipid Profile
? CK ?MB
? AST
? LDH 1 and LDH2
? Trop T and Trop I
? Myoglobin
? Homocysteine
? hs CRP
? LP-PLA2
? Creatine kinase (CK), formerly called creatinine
phosphokinase, is an intracellular enzyme found
in muscle cells. Muscles, including cardiac
muscle, use ATP as their energy source.
? Creatine Phosphate, which serves as a storage
form of energy in muscle, uses CK to convert
ADP to ATP.
? CK exceeds normal range within 4 to 8 hours of
myocardial injury and declines to normal within
2 to 3 days.
? There are three isoenzymes of CK, with the MB
isoenzyme (CK-MB) being highly specific for
injury to myocardial tissue.
? Myoglobin is an Oxygen-Storing Protein, that is
normally present in cardiac and skeletal muscle.
? It is a small molecule that is released quickly from
infarcted myocardial tissue and becomes
elevated within 1 hour after myocardial cell
death, with peak levels reached within 4 to 8
hours.
? It rapidly eliminates through urine (low
molecular weight).
? Because myoglobin is present in both cardiac and
skeletal muscle, it is not cardiac specific.
? The Troponin complex consists of three
subunits
? Troponin C
? Troponin I
? Troponin T
? These subunits are released during myocardial
infarction.
? Cardiac muscle forms of both troponin T and
troponin I are used in diagnosis of myocardial
infarction.
? Troponin I (and Troponin T) rises more
slowly than myoglobin
? This may be useful for diagnosis of
infarction, even up to 3 to 4 days after the
event.
? It is thought that cardiac Troponin assays
are more capable of detecting episodes of
myocardial infarction in which cel damage
is below that detected by CK-MB level.
Effects of Acute Myocardial
Infarction (AMI)
? The principal biochemical
consequence of AMI is
? The conversion from aerobic to
anaerobic metabolism
? With inadequate production of
energy(ATP) to sustain normal
Myocardial function.
? The ischemic area ceases to
function within a matter of
minutes, and
? Irreversible Myocardial cell
damage occurs after 20 to 40
minutes of severe ischemia.
Treatment
? Reperfusion
? (Re-establishment of blood flow)
? Thrombolytic therapy
?Streptokinase/ Urokinase
? Revascularization procedures
?Early Reperfusion (within 15 to
20 minutes) after onset of
ischemia can prevent necrosis.
?Reperfusion after a longer
interval can salvage some of the
myocardial cells that would have
died because of longer periods of
ischemia.
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
? The bal oon is then inflated and causes the stent to expand until it fits
the 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
improving the flow of blood.
Treatment 2) Angioplasty
?Bal oon catheter is passed through the guiding catheter to the area
near the narrowing. A guide wire inside the balloon catheter is then
advanced through the artery until the tip is beyond the narrowing.
? The angioplasty catheter is moved over the guide wire until the
balloon 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
sufficiently opened, the balloon catheter will be deflated and removed.
Treatment
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
? the "bypass graft" enables blood to reach your heart by flowing
around (bypassing)
the blocked portion of
the diseased artery.
The increased blood
flow reduces angina
and the risk of heart
attack.
Peripheral Arterial Disease (PAD)
Peripheral Arterial Disease (PAD)
? PAD refers to the obstruction of
large arteries in lower extremities
of leg
? It possess, inflammatory
processes leading to stenosis, an
embolism, or thrombus formation.
Risk of PAD
? Risk of PAD also increases in
individuals who are:
?Over the age of 50
?Male Obese
?With a family history of vascular
disease, heart attack, or stroke.
Symptoms OF PAD
? About 20% of patients with mild PAD may be
asymptomatic;
? Symptoms of PAD include:
? Pain, weakness, numbness, or cramping in muscles
due to decreased blood flow
? Sores, wounds, or ulcers that heal slowly or not at all
? Noticeable change in color (blueness or paleness) or
temperature (coolness) when compared to the other
limb
? Diminished hair and nail growth on affected limb and
digits.
Prevention Of Dyslipidemias
And Its
Consequences And Complications
?Get regular medical checkups
?Eat a Heart-Balanced healthy diet
?Control your blood pressure
?Check your Blood Cholesterol
?Don't smoke and drink Alcohol
?Exercise regularly
?Maintain a healthy weight
?Manage stress
THE HEALTHY PLATE
FOODS THAT LOWER LDL
CHOLESTEROL
1. Oats
2. Barley and Whole grains
3. Beans
4. Eggplant and okra
5. Nuts
6. Vegetable oils (canola, sunflower, safflower)
7. Apples, grapes, strawberries, citrus fruits
8. Soy
9. Fatty Fish
10. Fiber supplements
qEat meat sparingly
qAdd Fish to your diet
qGo for Nuts
qEat Fruits and Vegetables
qIncrease Complex Carbohydrates and fiber
qOpt for low-Fat dairy products
qCut down on Saturated fat in cooking
qAvoid Palm and Coconut oils ( Rich in SFAs)
qAvoid Trans Fats
qReduce Dietary Cholesterol
qReduce Salt intake
qWatch the Snacks
Blood Cholesterol levels increase
by eating these products
? Refined Sugars
? Beef
? Poultry
? Fish
? Milk
? Eggs
? Cheese
? Yogurt
EXERCISE
qAerobic exercise (jogging, swimming, brisk walking,
bicycling, etc)
STRESS REDUCTION STEPS
? Be Spiritual
? Balance All Actions
? Make and Fol ow Right protocols
? Be Planned and Organized
? Manage works based on priority
? Involve In work which you are chosen for
? Be Obedient and Have Patience
? Be Happy with what get
? Not expect too much in life
? Repent, Accept But Do Not Repeat
? Ventilate And Communicate
Summary To Prevent
? Eat right
? Watch your weight -even a modest drop in
weight can make a difference
? Be Active - start a program of light exercise
for at least 30-45 minutes every day
? Lower your stress levels. Practice stress
reduction techniques
? Stop smoking and drinking alcohol
? Be Spiritual
Avoid
Promote
Unhealthy eating
Healthy eating
Visit your doctor
Relaxation
regularly
Check your weight
Balance intake with output
Exercise regularly
Inborn Errors Of Lipid Metabolism
Inborn Error Of Enzyme
Abnormal
Lipid
Deficient/
Accumulation
Metabolism
Defect
Of
Sudden Infant
Acyl CoA
Acyl CoAs
Death Syndrome
Dehydrogenase
(SIDS)
Refsums Disease
-Phytanic Acid Phytanic Acid
Oxidase
Zellwegers
Peroxisomal
VLCFAs in
Syndrome
Oxidation
Peroxisomes
Inborn Error
Enzyme Defect
Abnormal
Lipid Storage
Accumulation Of
Disorders
Niemann Picks
Sphingomyelinase Sphingomyelin in
Disease
Liver and Spleen
Tay Sachs Disease Hexoseaminidase Gangliosides in
Defect
Tissues
Gaucher's Disease eta Glucosidase Glucosides in Tissues
Inborn Enzyme
Abnormal
Error
Defect
Accumulation Of
Krabbe's Beta
Disease Galactosidase Galactocerebroside
Farbers Ceramidase
Ceramides
Disease
Role Of Insulin In Lipid Metabolism
? Insulin
? Stimulates LPL
? increased uptake of FA
from Chylomicrons and
VLDL
? Stimulates Glycolysis
? increased glycerol
phosphate synthesis
? increases esterification
? Induces HSL-phosphatase
? inactivates HSL
? Inhibits Lipolysis
? Net effect: TG storage
? Lack of Insulin
?Free Fatty acids build up in
blood
?Can lead to excess Acetoacetic
acid production and buildup of
acetone (acidosis, which can
lead to blindness and coma)
Insulin
Most Cel s
amino
Control
Protein synthesis
acids
Muscle
Glucose uptake
Glycogen synthesis
Gastrointestinal
hormones
triglycerides
Adipose
Glucose uptake
Glycerol production
Triglyceride breakdown
Amino
Pancreas Insulin
Triglyceride synthesis
acids
Beta cells
Liver
Blood
Glucose uptake
glucose
glucose
Glycogen synthesis
Fatty acid synthesis
Glucose synthesis
Brain
No effect
Feedback
Glucagon
Control
Adipose
Triglyceride breakdown
Fatty acids
? Triglyceride storage
Exercise
Amino acids
Pancreas
Alpha cells
Liver
Glycogen breakdown
Glucose synthesis
Blood glucose
Epinephrine
Glucose release
(stress)
Brain
No effect
Types Of Lipases
S.
Type Of Lipase
Location
No
Action Upon
1
Lingual Lipase
Mouth
Dietary TAG
(Insignificant Action)
2
Gastric Lipase
Stomach
Dietary TAG
(Insignificant Action)
3
Pancreatic Lipase
Smal Intestine
Dietary TAG
(Significant Action)
S. Type Of Lipase
Location
No
Action
4
Lipoprotein Lipase
Endothelial Lining
Of Blood Vessels
Lipoprotein TAG
5
Hormone Sensitive
Adiposecytes
Lipase
Hydrolyzes
Stored TAG
6
Hepatic Lipase
Liver
TAG
7
Phopshpholipase A2 Small Intestine
Phospholipids
Questions
Q.1. Describe in details the digestion
& absorption of dietary form of lipids
& add a note on Steatorrhoea
OR
Q.1.What are different forms of
dietary lipids? How the dietary lipids
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
chain fatty acid.
OR
Q.2. Define -oxidation of fatty acid. Explain the
oxidation of Palmitate and calculate its
energetics./Fate of fatty acids in human body?
OR
Q.2. Explain -oxidation of odd chain fatty acids.
Q.3. What is Lipogenesis? Describe in
details the De-novo synthesis of fatty
acid.
OR
Q.3. Explain the Extra mitochondrial
synthesis of Palmitate.
Q.4. What is ketoacidosis? Give fate &
formation ketone bodies.
? Short Notes
? Transport & storage of lipids / Role
lipoproteins.
? Emulsification & its significance / Role of
Bile salts in digestion & absorption of lipid.
? Lipolysis / Role of Hormone Sensitive
Lipase/Adipose tissue metabolism.
? Clearing factor / Lipoprotein
lipase.
? Multi-enzyme complex of Fatty
acid biosynthesis / Fatty acid
synthesis complex.
? Microsomal synthesis of fatty acid.
? Fatty liver /Lipotropic factors.
? Cholesterol-outline of Biosynthesis.
? Hypercholesterolemia ? causes &
consequences
? Atherosclerosis
? Myocardial Infarction
? Enumerate the Inborn errors related to
lipid metabolism.
? Transport & Excretion of Cholesterol/
Reverse transport of cholesterol.
? Fate & formation of Acetyl?CoA
? Fate of Propionyl-CoA
? Role of Carnitine in Lipid metabolism
? Role of Liver in Lipid metabolism.
? TAG metabolism.
? Ketonemia & Ketonuria
? Represent the schematic structure of
lipoprotein.
? Role of Citrate in lipid metabolism.
? Role of Carnitine in lipid metabolism.
? Hormonal Influence in Lipid
Metabolism
? Catabolism of Cholesterol.
? CETP activity
? HDL2 and HDL 3
? Zellweger & Refsum's disease.
? Mixed Micelle
? Four types of Lipoproteins & their role
? Hyperlipoproteinemias
? Hypolipoproteinemia's
? Different types of Lipases & their action.
Biochemistry Department
This post was last modified on 05 April 2022