Download MBBS Biochemistry PPT 53 Lipid Metabolism Lecture Notes

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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