Lipids & lipid metabolism

By: Mr Metages Ayele. (BSc, MSc In Medical Biochemistry)

JU, Jimma, Ethiopia 2016EC.
 Outline
Introduction
Classification of lipid
Digestion and absorption of lipid
Maldigestion and malabsorption of lipid
Lipid metabolism
De novo synthesis of fatty acids
Triacylglycerol mobilization (Lipolysis)

Ketone bodies
Ketogenesis & Ketolysis
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 Introduction
Lipids are heterogeneous group of organic substances
 Containing mainly of C, H & O and in some cases N & P.

They are insolubility in water.

 But soluble in non – polar/organic solvents like chloroform, ethene
& benzene.

Widely distributed in nature.

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Lipids are formed mainly from alcohol & fatty acids
through ester linkage.

Most membrane lipids are amphipathic; Have non-polar &

polar end.
Found either as: compartmentalized (in membrane),
droplets (in adipocytes) & lipoprotein particles.

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 Classification of lipids
Based on lipid function as:
o Storage lipids
o Structural lipids
o Other
Based on lipid composition as:
o Simple lipids
o Complex lipids
o Derived lipids.

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 Storage Lipids
Fats & Oils (TAG) and Waxes
Fats and oils: used as stored forms of energy.
o Fatty acids (FA):
Hydrocarbon derivatives are aliphatic carboxylic acids
Found in nature as esterified forms
Exists in body free or as fattyacyl esters
Most contain an even number of carbon atoms
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o FAs fill two major roles in the body:
As components of membrane lipids & major stored fat
o There are 2 common alcohols which present in lipids
I. Glycerol
A trihydric alcohol (containing three OH groups)
Colorless, viscous, oily liquid with sweet taste
On esterification with FAs, it gives MAG, DAG& TAG

II. Sphingosine
An 18–C amino alcohol with unsaturated hydrocarbon chain
Forms a primary part of sphingolipids.
Synthesized in the body from serine and palmitic acid
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 Simple Lipids
o A fatty acid ester of d/t alcohols and carries no other
substance:
Neutral fats and oils (Triglycerides)
Waxes
Cholesterol esters: esters of fatty acid with cholesterol
Vit A esters: palmitic acid esters of Vit A (Retinol)

Vit D esters: Stearic acid esters of Vit D

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  Neutral fats and oils (Triglycerides)
o Uncharged due to absence of ionizable groups in it
o The most abundant lipids in nature
o They are esters of glycerol with various fatty acids

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Types of triglycerides
Simple triglycerides
o If the 3 FAs connected to glycerol are of the same type, e.g.,
tripalmitin

Mixed triglycerides
o If the 3 FAs connected to glycerol are d/t types e.g., stearo-diolein
and palmito-oleo-stearin

o Natural fats are mixtures of mixed with small amount of simple

triglycerides.

 The common FAs in animal fats are: Palmitic acid C 16:0, Stearic
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C 18:0 & Oleic acids C 18:1
o The main difference between fats and oils is:
Oils being liquid at room temperature,
Fats are solids at room temperature
Oils have larger percentage of unsaturated FAs than fats that has
mostly saturated FAs

o Physical properties of fat and oils:

Freshly prepared fats and oils are colorless, odorless and tasteless.
Fats have specific gravity <1
Fats are insoluble in water, but soluble in organic solvents.
Melting points of fats are usually low, but higher than the
solidification point.
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Chemical Properties of fats and oils
Hydrolysis
o They are hydrolyzed into their constituents (free FAs & glycerol)
by the action of super heated steam, acid, alkali or enzyme.

Saponification
o Alkaline hydrolysis produces glycerol and salts of FAs (soaps)
o Soaps cause emulsification of oily material which help easy
washing of the fatty materials.

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Halogenation
o Neutral fats containing unsaturated FAs have the ability of
adding halogens at the double bonds. e.g. Iodine – iodination
o It is a very important property to determine the degree of
unsaturation of the fat or oil that determines its biological
value.

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Hydrogenation or hardening of oils
o It is a type of addition reactions accepting hydrogen at the double
bonds of unsaturated fatty acids.
o It is done under high pressure of H and is catalyzed by finely
divided nickel or copper and heat.
o It is the base of hardening of oils (margarine manufacturing), e.g.,
change of oleic acid of fats (liquid) into stearic acid (solid)

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Oxidation (Rancidty)
o A physicochemical change in the natural properties of oils
and fat leading to the development of unpleasant odor, taste

or color.

o Developed after exposure to atmospheric oxygen, light,

moisture, bacterial or fungal contamination and/or heat.

 Saturated fats resist rancidity more than unsaturated fats that

have double bonds.

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 Waxes
o Solid simple lipids.
o Contain a monohydric alcohol, with a higher MW than
glycerol.
o Esterified to long chain FAs.
o Insoluble in water, but soluble in fat solvents.
o They are not easily hydrolyzed as fats, indigestible by lipases
and very resistant to rancidity.
o Thus they are of no nutritional value.
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o Waxes are widely distributed in nature:
The secretion of certain insects as bees-wax,
Protective coatings of the skins and furs of animals
Leaves and fruits of plants
o They are classified into:
I. True waxes e.g., bees wax

II. Wax like compounds e.g., very complex mixture

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 Differences between neutral lipids and waxes
Waxes Neutral lipids
Digestibility: Indigestible (not Digestible (hydrolyzed by lipase)
hydrolyzed by lipase)

Type of alcohol: Long-chain monohydric Glycerol (trihydric) + 3 fatty acids

alcohol + one fatty acid

Type of FAs: Fatty acid mainly palmitic or Long and short chain fatty acids
stearic acid

Rancidability: Never get rancid Rancidible

Nature at room Hard solid Soft solid or liquid

temperature

Saponification Non saponifiable Saponifiable

Nutritive value: No nutritive value Nutritive

Example: Bee & carnuba waxes Butter and vegetable oils

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 Complex Lipids
o Lipids that contain additional substances, beside FA and alcohol
e.g., sulfur, phosphorus, amino group, carbohydrate or proteins

o According to the nature of the additional group, they can be

classified as:

 Phospholipids
 Sulfolipids
 Glycolipids
 Amino lipids
 Lipoproteins
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Phospholipids (PL)
o They are compound lipids, which contain phosphoric acid
group in their structure.

 Esters of FAs containing phosphoric acid residues,

nitrogenous bases & other substituent:
 Phosphatidyl choline (Lecithin)
 Phosphatidyl ethanolamine (Cephalin)
 Phosphatidyl inositols (Lipositols)
 Phosphatidyl serine
 Plasmalogens
 Sphingomyelins
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Importance of PLs:
o Components of cell membranes, lipoprotein coat, myelin sheath
of nerves
o Important in digestion and absorption of neutral lipids and
excretion of cholesterol in the bile.
o Important in blood clotting and platelet aggregation.
o Provide lung alveoli with surfactants that prevent its irreversible
collapse.
o Important role in signal transduction across the cell membrane.
o Source of polyunsaturated FAs for synthesis of eicosanoids.
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Sources of PLs:
 Found in all cells, milk and egg yolk in the form of lecithin.
PLs are composed of:
 Fatty acids.
 Nitrogenous base (choline, serine, threonine, ethanolamine).
 Phosphoric acid
 Fatty alcohols (glycerol, inositol or sphingosine).

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o PLs are classified into 2 groups, according to the type of the alcohol
they contain:

I. Glycerophospholipids: Derivatives of phosphatidic acids that are

the simplest type of PLs.

Include: Phosphatidic acids, lecithins, cephalins, plasmalogens, inositides,

cardiolipin

II. Sphingophospholipids: Contain sphingosine as an alcohol, two

nitrogenous bases: Sphingosine and choline  named

sphingomyelins.

Contain sphingosine base, one long-chain fatty acid, choline and

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Glycolipids
o Lipids that contain carbohydrate residues with
sphingosine as an alcohol and a very long-chain FA (24
carbon series).
o According to the number & nature of the CHO residue(s)
present in, they are classified in to:
Cerebrosides
Sulfatides (sulfated cerebrosides)
Gangliosides
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Lipoproteins
o They are lipids combined with proteins in the tissues
o Lipid component is PL, cholesterol or TAG
o Lipoproteins include:
Structural lipoproteins: widely distributed in tissues e.g.,
surfactant & rhodopsin of rods.

Transport lipoproteins: present in blood plasma; composed

of apolipoprotein and d/t types of lipids. E.g., Chylomicron,
VLDL, LDL & HDL
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Derived lipids
o They are derived from lipids (simple or complex) or precursor of
lipids, Example: fatty acids, steroids, cholesterol, vitamin A and D

Fatty acids
 Are aliphatic mono-carboxylic acids.
 Mostly obtained from the hydrolysis of natural fats and oils.
 Mostly have straight chain
 Have the general formula R-(CH2)n-COOH.
 In this formula "n" is mostly an even number of carbon atoms (2-
34) with a few exceptions that have an odd no.
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Classification of FA:
o Based on the total number of carbon atom: even & odd
chain FA
o Based on the length of hydrocarbon chain as: short chain
(4–6), medium chain (8–12), long chain (12–24) & very
long chain (>24)
o Based on the degree of saturation of hydrocarbon chain:
saturated & unsaturated

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Saturated FAs
o Contain no double bonds with 2 – 24 or more carbons
o Solid at room temperature except if they are short chained
o They may be even/odd numbered
o Have the molecular formula: CnH2n+1COOH

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Unsaturated Fatty Acids
 Contain double bond

 Monounsaturated fatty acids contain one double bond

(CnH2n–1COOH)

 Polyunsaturated Fatty acids contain more than one double

bond (CnH2n–more than 1COOH)

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Digestion and absorption of lipid

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 Digestion and absorption of lipid
 TAGs (containing FAs of short & medium chain length) are
catalyzed by:

Acid stable lingual & gastric lipase.

 Emulsification of dietary lipid in the SI occurs in duodenum
by:

Bile salts and peristalsis.

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Degradation of dietary lipids by pancreatic enzymes
 TAG catalyzed by an esterase, pancreatic lipase  2–MAG &

free FAs

 Cholesteryl ester are hydrolyzed by pancreatic cholesterol

esterase, which produces cholesterol plus free FAs.

 Phospholipid degradation: Phospholipase A2 removes one FA

from C–2 of a PL, leaving a lysophospholipid. The remaining FA

at C–1 can be removed by lysophospholipase, leaving a

glycerylphosphoryl base.
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Lipid digestion controlled by:
o Cholecystokinin (CCK):
Produced by lower duodenum and jejunum
It acts on the gallbladder (causing it to contract and release bile);
on the exocrine cells of the pancreas (causing them to release
digestive enzymes) &

it also decreases gastric motility.

o Secretin:
Causes the pancreas and the liver to release a solution rich in
bicarbonate that helps neutralize the pH of the intestinal contents.
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Absorption of lipids by intestinal mucosal cells/enterocytes
o Free FAs, free cholesterol, and 2–MAG are the primary products of lipid

digestion in the jejunum.

o These, plus bile salts and fat-soluble vitamins (A, D, E, and K), form mixed

micelles–disk shaped clusters of amphipathic lipids.

o These particles approach the primary site of lipid absorption, mucosal cell.

o The hydrophilic surface of the micelles facilitates the transport of the

hydrophobic lipids.

o Bile salts are absorbed in the ileum.

o Short- and medium chain length FAs do not require the assistance of mixed
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micelles for absorption by the intestinal mucosa.
Resynthesis of TAG and cholesteryl esters occurs in the
ER of enterocytes:

o FAs & 2–MAGs are converted to TAGs by TAG synthase.

o Lysophospholipids are reacylated to form PLs by a family of
acyltransferases, and cholesterol is esterified to a FA
primarily by acyl CoA:cholesterol acyltransferase.

o Short and medium chain length FAs are not converted to

their CoA derivatives, and are not reesterified to 2–MAG.
Instead, they are released into the portal circulation.
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Lipid malabsorption:
o Resulting in increased lipid
(including the fat soluble vitamins
and essential fatty acids) in the
feces (that is, steatorrhea),
o Caused by disturbances in lipid
digestion and/or absorption
including CF (causing poor
digestion) and shortened bowel
(causing
06/20/2024 decreased absorption). 38
 Lipid metabolism

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06/20/2024 40
 De novo synthesis of fatty acids
o In adult humans, FA synthesis occurs primarily in the liver
& lactating mammary glands and, to a lesser extent, in
adipose tissue.
o This cytosolic process incorporates carbons from acetyl
coenzyme A (CoA) into the growing FA chain,
o Utilize ATP and reduced nicotinamide adenine dinucleotide
phosphate (NADPH).

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o The 1st step is the transfer of acetate units
from mitochondrial acetyl CoA to the cytosol.

o Mitochondrial acetyl CoA is produced by the

oxidation of pyruvate and by the catabolism
of FAs, ketone bodies, and certain AAs.

o Only the acetyl portion enters the cytosol.

o cytosolic citrate may be viewed as a high-

energy signal.

o The increase in both ATP and citrate

enhances this pathway.

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o The carboxylation of acetyl CoA to form malonyl CoA is
catalyzed by acetyl CoA carboxylase, and requires CO2 &
ATP.
o The coenzyme is the vitamin, biotin is required.

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o The remaining series of reactions of FA synthesis in
eukaryotes is catalyzed by the multifunctional, dimeric
enzyme, fatty acid synthase (FAS).
o Each FAS monomer is a multicatalytic polypeptide with
seven different enzymic activities plus a domain that
covalently binds a molecule of 4'–phosphopantetheine
carries acyl units on its terminal thiol (–SH) group during
FA synthesis. Referred to as the acyl carrier protein (ACP).

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Seven steps of De Novo synthesis of FA:
1. A molecule of acetate is transferred from acetyl CoA to the –SH
group of the ACP Domain.
2. This 2C fragment is transferred to the thiol group of a cysteine
residue on the enzyme.
3. The now-vacant ACP accepts a 3C malonate unit from malonyl
CoA Domain.
4. The acetyl group condenses with the malonyl group & the CO2
is released. Domain: 3-Ketoacyl-ACP synthase.
5. The keto group is reduced to an alcohol. Domain: 3-
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KetoacylACP reductase.
6. A molecule of water is removed to introduce a double bond b/n C
2 & 3 (the α & β-Cs).

7. The double bond is reduced.

This cycle of reactions is repeated 6 more times, each time

incorporating a 2C unit (derived from malonyl CoA) into the
growing FA chain at the carboxyl end.

Palmitoylthioesterase cleaves the thioester bond, releasing a fully

saturated molecule of palmitate (16:0).

Further elongation by the addition of 2C units occurs in the SER.

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Major sources of the NADPH
required for FA synthesis:
o The HMP pathway
o The cytosolic conversion of malate to
pyruvate

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 Triacylglycerol mobilization (Lipolysis)
Triacylglycerol:-

 Is important in furnishing energy in animals

 Have the highest energy content (> 9kcal/mole)
 Provide more than half the energy need of some organs like
o Brain, liver, heart, and resting skeletal muscle

o When energy supply from diet is limited, body responds through

hormonal signals transmitted to adipose tissue by release of

 Glucagon, epinephrine, or adrenocorticotropic hormone

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o The hormones bind to the plasma membranes and stimulate
hormone sensitive TAG lipases.

o These lipases hydrolyze the TAGs at position 1 or 3 to produce: -

DAG & FA, which is the rate limiting step.

 DAG lipases hydrolyze the DAG to MAG & FA.

 MAG lipases hydrolyze MAG to FA & glycerol.

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Fate of glycerol
o The glycerol released during TAG degradation cannot be
metabolized by adipocytes b/c they lack glycerol kinase.
o Rather, glycerol is transported through blood:
 To the liver, where it can be phosphorylated Glycerol
phosphate.

 It used to form TAG in the liver, or can be converted to DHAP.

 DHAP can participate in glycolysis or gluconeogenesis

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 Oxidation of fatty acid
Types of oxidation of FAs:
I. β-Oxidation
o Major mechanism, occurs in the mitochondrial matrix
o Two carbon units are released as acetyl CoA per cycle
II. α-oxidation
o Predominantly takes place in liver and brain
o One carbon is lost in the form of CO2 per cycle
III.ω-oxidation
o Minor mechanism
o
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B/c important in conditions of impaired β oxidation 52
β-oxidation
o The principal pathway for the catabolism of FAs.
o It is oxidation of FA at the β carbon atom with successive
removal of 2 carbon atoms as acetyl CoA.

o Site: Mitochondrial matrix:

 Liver, heart (80% of its fuel), lung, muscle & kidney
o Brain cells have β-oxidation ability but BBB:-
 Prevent the entrance of FAs to these cells,
 Brain depends on ketone bodies***
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Activation of FAs & their transport to
mitochondrion

o FAs are activated to their CoA derivative, using ATP as the

energy source.

 Carboxyl group is 1st activated to an enzyme bound,

High energy acyl adenylate intermediate formed
The acyl group is then transferred to CoA By the
enzyme fatty acyl CoA synthetase (fatty acid thiokinase).
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Acyl CoA Transport & Role of Carnitine
o FAs with chain lengths of 12 or fewer Cs enter in to the
mitochondria without the help of membrane transporters.

o Those with 14 or more Cs cannot pass directly through the

mitochondrial membranes

o They must first undergo the three enzymatic rxn’s of the

carnitine shuttle.

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o CPT I in the OMM transfers fatty acyl group to carnitine &
releases CoASH.

o The fatty acyl carnitine is translocated into the

mitochondrial matrix by translocase, as carnitine moves
out;

o CPT II on the IMM transfers:

 The fatty acyl group back to CoASH to form fatty acyl CoA
in the matrix.

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06/20/2024 57
Mitochondrial Oxidation of FAs: Takes place in three stages

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1st stage of β-oxidation
o Successive removal of 2C from acyl-CoA molecules
starting from the carboxyl end.

o The chain is broken b/n the α (2) & β (3) C atoms hence the
name β-oxidation.

o The 2C units formed is acetyl CoA

o Removal of 4 hydrogen atoms (2 pairs of e¯ & 4 H+) from
the fatty acyl moiety by dehydrogenases.

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o 2nd stage TCA cycle

 Acetyl groups of acetyl-CoA are oxidized to CO2 in

TCA cycle

o 3rd stage ETC

 NADH & FADH2 donate electrons to ETC through

which e-s pass to oxygen with the concomitant
phosphorylation of ADP to ATP

 Energy released by FA oxidation is thus conserved as

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ATP.
β- Oxidation of saturated FAs
Contains 4 Basic Steps:
o Step I: Unsaturation (dehydrogenation)
 Catalyzed by acyl-CoA dehydrogenase
 Coenzyme for this rxn is a flavoprotein (FAD) as a
prosthetic group to form FADH2

o Step II: Hydration

 Catalyzed by enoyl-CoA Hydratase (crotonase), which
helps addition of H2O to saturate double bond.
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o Step III: Oxidation (β-oxidation)- dehydrogenation
 By β-Hydroxyacyl CoA dehydrogenase & NAD+ to Produce
NADH

o Step IV : Splitting of active acetate- (chain breakage)

 By Thiolase (acyl-CoA acetyltransferase)
 Splits acyl CoA into Acetyl CoA & Acyl CoA, w/c is shorter
than the first one by 2 carbon atoms

β-Oxidation is repeated until the whole FA is broken into

acetyl CoA; w/c are then oxidized to CO2 & H2O in Krebs’
cycle
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06/20/2024
Steps of -Oxidation 63
Oxidation of unsaturated FAs
o In β-oxidation of saturated FAs, a trans double bond is created b/n
α & β carbons
o For unsaturated FAs to undergo the β-oxidation spiral, cis double
bonds must be isomerized to trans double bonds
o The double bond must be reduced b/n the 2 nd & 3rd C’s during β-
oxidation
o Two auxiliary enzymes are needed: isomerase & reductase.

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o The process is illustrated for the PUFA linoleate
o Linoleate undergoes β-oxidation until double bond
 B/n C-3 & C-4 near the carboxyl end &

 The other is b/n C-6 & C-7

o An isomerase moves the double bond from the 3,4 position to
2,3 position, so that it is trans and β–oxidation continues

o When a conjugated pair of double bonds is formed at positions

2 & 4, NADPH-dependent reductase reduces the pair to one
trans double bond at position 3
 Then isomerization & β-oxidation resume.
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 Oxidation of Linoleate

06/20/2024 66
Oxidation of FAs With Odd No of C-Atoms
o FAs containing odd number of carbon atoms undergo β-
oxidation producing acetyl CoA, until the last spiral when 5
carbons remain in the fatty acyl CoA.
o In this case, cleavage by thiolase produces Acetyl CoA &
3-carbon fatty acyl CoA  Propionyl CoA

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Carboxylation of
propionyl CoA yields:
o Methylmalonyl CoA, which is
ultimately converted to:

 Succinyl CoA
o Propionyl CoA also arises
from oxidation of branched
chain AAs.

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o The propionyl CoA to succinyl CoA pathway is
 A major anaplerotic route for TCA cycle
 Used in the degradation of valine, isoleucine& other cp’s
 In the liver, this route provides precursors of oxaloacetate
 Thus, this small proportion of the odd-carbon number FA
chain

Can be converted to glucose

 In contrast, the acetyl CoA formed from β-oxidation of even
chain number FAs in the liver either enters the TCA cycle, or
converted to ketone bodies.
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Bioenergetics of FA oxidation
o Yield of ATP during β-oxidation of one molecule of
palmitic acid (16 C):

 Repeated 7 times producing 8 acetyl CoA

 In each time, FADH2 & NADH + H+ is produced and will

be transported to the respiratory chain where:
FADH2  2 ATP
NADH + H+  3 ATP
So 7 times = 7 x 5 ATP  35 ATP
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o Each acetyl CoA which is oxidized in TCA cycle gives 12
ATP
 8 x 12 ATP  96 ATP

o Two high energy phosphate bonds are utilized in the

activation of FA
o Energy gain = Energy produced – Energy utilized
= 35 ATP + 96 ATP – 2 ATP
= 131 ATP – 2 ATP

o Energy gain = 129 ATP

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Importance of β-Oxidation
o Source of energy
o Production of acetyl CoA
o Ketone bodies formation
Regulation of β-Oxidation
o Cells’ requirements for energy , i.e., by levels of ATP &
NADH
 When energy increases ( ATP ), β-oxidation is inhibited &
vice versa
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 Ketone bodies (KBs)
 Ketone bodies are water-soluble molecules/cpds that
contain the ketone groups produced from FAs by the liver.
 Three substances are collectively known as “ketone bodies”
(or “acetone bodies”).
Acetoacetate, acetone & β-OH butyric acid
 Acetoacetate continually undergoes spontaneous
decarboxylation to produce acetone

06/20/2024 73
 Ketonaemia: Rise of KBs in blood above normal level.

 Ketonuria: When the blood level of KBs rises above the renal
threshold, they are excreted in urine.
 Ketosis: Accumulation of abnormal amount of KBs in tissues
& body fluids.
 Ketoacidosis:
 Acetoacetic acid & β-OH-butyric acid are moderately strong acids.
They are buffered when present in blood & tissues, loss of buffer
cations, which progressively depletes the alkali reserve↓ causing
ketoacidosis.
06/20/2024 74
 Note: This may be fatal in uncontrolled DM.
Causes of ketoacidosis
 Non- pathological state
 Prolonged Starvation

 Carbohydrate poor diet

 High fat diet

 After severe exercise in the post-absorptive state.

 In Pathologic States
 In DM: In uncontrolled DM, there could be a pathological state
of ketosis (or ketoacidosis or even ketoacidotic coma) that may
be fatal. In diabetic ketosis, the ketonuria causes loss of Na & K
06/20/2024 75
 Ketone body formation in liver (KETOGENESIS)
 Liver is the only organ w/c produces KBs, occur in
mitochondria and add to the blood.

 Extrahepatic tissues can pick up KBs from the circulating blood

& utilize them as respiratory substrates.

 Steps:
 Formation of Aceto-acetyl-CoA: Two acetyl-CoA condensed to form
Aceto-acetyl CoA.  catalyzed by thiolase enzyme.

 Formation of Acetoacetate: Acetoacetate is the first KB to be formed.

This can occur in two ways: By deacylation & HMG-CoA pathway
06/20/2024 76
Formation of Acetone: Acetone is formed from
acetoacetate by spontaneous decarboxylation (Non-
enzymatic).
Formation of β-OH Butyrate: Acetoacetate once formed
is converted to β-OH-butyric acid; the reaction is
catalyzed by the enzyme β-OH butyrate dehydrogenase,
which is present in liver and also found in many other
tissues.

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06/20/2024 78
 Utilization of KBs (KETOLYSIS)

 KBs are utilized by extrahepatic tissues as “fuel”.

 Steps of ketolysis:
Activation of Acetoacetate:

• Two reactions take place in extrahepatic tissues which

activate acetoacetate to form aceto-acetyl-CoA,
Action of acetoacetate with succinyl-CoA: Major Pathway by
which acetoacetate is activated in extrahepatic tissues.
 Catalysed by the enzyme CoA transferase (thiophorase) to
forming acetoacetyl-CoA & succinate
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  Second mechanism: Activation of acetoacetate with ATP and CoA-
SH, catalysed by the enzyme Acetoacetyl-CoA synthetase. This is
probably not a major pathway

 Fate of β-OH-Butyrate
 β-OH-butyrate may be activated directly in extrahepatic tissues by a
synthetase.
 β-OH-butyrate can be converted back to “acetoacetate” by the enzyme
β-OH-butyrate dehydrogenase & NAD+, as the reaction is reversible.

 Fate of acetone:
 Acetone is difficult to be oxidized in vivo. Experimental evidences
show very slow rate of utilization. Excess of acetone can be breathed
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out and also excreted in urine.
 Regulation of ketogenesis
 Ketogenesis speeds up or slows down depending on three
important factors:
 The level of circulating F.F.As: For example, in starvation
the insulin / glucagon ratio decreases, causing increased
lipolysis in adipose tissues.
 Rate of entry of F.F.As into the liver: If F.F.As are entering
the liver cells in low concentrations, they will nearly all
esterified into TGs and transported out of the liver in very
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low density lipoproteins (VLDL).