LIPID METABOLISM _2

CHEM 3
MMC-CAST_EDLUGUE
Ketone Body Production and
Metabolism
o Ketone bodies refers to the three biosynthetically
related compounds :
• acetoacetate
• β hydroxybutyrate
• acetone
• Produced in the liver from acetyl CoA substrate
and carried to extrahepatic tissues where
acetoacetate and β-hydroxybutyrate are
metabolized to produce energy.
Acetone - cannot be metabolized and is readily exhaled.
Structure of Ketone Bodies

Acetoacetate and Acetone – true ketones

Ketone Bodies
 Ketone Body Synthesis (
Ketogenesis)
• synthesized exclusively in liver mitochondria from
acetyl CoA or acetoacetyl CoA
• Acetyl CoA
- obtained by oxidation of pyruvate, fatty acids or the
ketogenic amino acids (lysine, leucine, tyrosine)
• Acetoacetyl CoA
- produced by condensation of two molecules of acetyl
CoA by thiolase
 Steps of Ketone Body Synthesis
( Ketogenesis)
Step 1.
↑ acetyl CoA concentration → Acetoacetyl CoA
 Steps of Ketone Body Synthesis
( Ketogenesis)
Step 2.
• Acetoacetyl CoA combines with another acetyl CoA
molecule to produce HMG-CoA (3-hydroxy-3-
methylglutaryl CoA).

Enzyme - HMG CoA synthase

 Steps of Ketone Body Synthesis
( Ketogenesis)
Step 3.
HMG CoA undergoes an aldose-lyase reaction, cata-
lyzed by HMG CoA lyase. The cleaved products are
acetoacetate and acetyl CoA.
 Steps of Ketone Body Synthesis
( Ketogenesis)
Step 4.
Acetoacetate is reduced by NADH to form β -
hydroxybutyrate by the enzyme β -hydroxybutyrate
dehydrogenase, and a small fraction undergoes
spontaneous decarboxylation to form acetone.
 Ketone Body Oxidation
• The two main ketone bodies, acetoacetate and β -
hydroxybutyrate, are water soluble.
- readily transported from the liver to various tissues, -
which use them as important sources of energy, e.g.
skeletal muscles, cardiac muscle, renal cortex, etc.
• Site : mitochondria of these tissues

Oxidation of some ketogenic amino acids directly

yields acetoacetate.
Acetoacetyl CoA can be directly formed by ℬ-
oxidation of fatty acids
 Ketone Body Oxidation

 First, oxidation of beta-hydroxybutyrate produces

acetoacetate, catalyzed by beta-hydroxybutyrate
dehydrogenase

 Acetoacetate is activated to acetoacetyl CoA via the

mitochondrial thiophorase with succinyl CoA as coenzyme.

 Acetoacetyl CoA is cleaved by thiolase to yield two acetyl CoA

molecules, which are oxidized in TCA cycle.

Acetone, however cannot be metabolized and most is

exhaled through lungs.
Ketone Body Oxidation
Ketone Body Oxidation
 Excessive Production of Ketone
Bodies
↑ synthesis of ketone bodies
- starvation
- diabetes mellitus
∴ exceeds the ability of extrahepatic tissues to utilize
them

∴ get accumulated in blood leading → ketonaemia and ketonuria

∴ Ketosis = ↑ levels of ketone bodies in the body tissues

Excessive Production of Ketone
Bodies
NB. Any substrate, including glucose, that is
degraded to acetyl CoA in the liver can be converted
to ketone bodies
NB. ketogenesis is usually associated with excessive
fatty acid oxidation, which occurs most notably in
starvation and diabetes mellitus
Excessive Production of Ketone
Bodies
Excessive Production of Ketone
Bodies
Starvation
• low insulin : high glucagon state
• causes flow of fatty acids from the adipose tissue and
to the liver, where they become a major energy source
• Excessive generation of acetyl CoA ⍉ be fully handled
by TCA cycle because of the following reasons:
- Oxaloacetate depletion
- ↑ beta- oxidation → depletion of oxaloacetate ∵ the excess of
NADH produced converts it to malate = ↓ oxaloacetate ∴ limits
activity of TCA cycle
- Exhanced gluconeogenesis
- Oxaloacetate is directed towards glucose synthesis which
exacerbates the dearth of oxaloacetate and retards TCA cycle
Excessive Production of Ketone
Bodies
Excessive Production of Ketone
Bodies
Diabetes Mellitus
• most common cause of ketosis
• type 1 diabetes have little or no plasma insulin and the
insulin : glucagon ratio falls very low in decompensated
patients, resulting in overproduction of ketone
• Acetoacetate and beta-hydroxybutyrate decrease the pH of
blood and cause metabolic acidosis ( diabetic ketoacidosis )
• type 2 diabetes, ketoacidosis is relatively rare but may be
precipitated by a major stress, such as myocardial infarction.
• Production of acetone being significantly enhanced
 smell in the patient’s breath is a valuable aid to diagnosis of
diabetic ketoacidosis.
Excessive Production of Ketone
Bodies
Other Causes of Ketosis
• Alcoholism
• carbohydrate deficiency
• toxaemia of pregnancy
• prolonged labour
• overdose of salicylates and methanol.
Excessive Production of Ketone
Bodies
Dangers of Ketosis
• Ketosis causes metabolic acidosis and loss of sodium and
potassium ions from the body
• Large amounts of ketone bodies are excreted in urine, and
because of their anionic character they also carry away Na+
• Uncontrolled diabetes is accompanied by an osmotic diuresis.
Moreover, insulin increases potassium uptake by cells, therefore
lack of insulin in diabetes leads to release of potassium, which is
then uncontrollably lost in urine.
• Loss of circulating Na +may aggravate acidosis, because the Na+
depletion often results in decrease in circulatory bicarbonate ion
concentration.
• One may view this problem in terms of ketone bodies displacing
bicarbonate ions even if Na+ concentration remains constant
Regulation of Ketogenesis
 Availability of fatty acids
 Entry of fatty acid into mitochondrial matrix
- Carnitine acyl CoA transferase-I regulates entry of fatty
acids into mitochondrial matrix for oxidation
 Channelization of acetyl CoA into ketogenesis
- acetyl CoA formed by beta-oxidation has a choice between
progressing into TCA cycle, fatty acid biosynthesis, or
ketogenesis or even cholesterol synthesis.
TCA cycle is impeded and acetyl CoA is not used for
biosynthetic activity during fasting. This results in
channelization of acetyl CoA into ketogenesis.
 Effect of hormones: Insulin inhibits and glucagons stimulate
ketogenesis
 Cholesterol
• Cholesterol (in Greek, chole means bile, steros means
solid, ol means alcohol) is the most important sterol in
animal cells.
• It is the only important membrane steroid in animals
and humans.
• In a 70kg man, approximately 140 g cholesterol is
present, the majority of which is “free” (unesterified)
cholesterol in the cellular membranes.
• Cholesterol is most abundant in those tissues that
contain large amounts of membrane lipids, namely the
nervous system; brain contains approximately 30 g
cholesterol.
 Cholesterol
Cholesterol molecule (27 carbons) comprises a non-aromatic ring
system known as cyclopentano- perhydrophenanthrene ring,
which is decorated with a hydroxyl group, two methyl groups and
a branched hydrocarbon chain.
The hydroxyl group, present at C-3 of the ring, is esterified with a
long-chain fatty acid, to form cholesterol ester (CE), which is used
as intracellular storage form of cholesterol.
 CE is abundant in some steroid hormone producing tissues,
particularly the adrenal cortex where the cholesterol ester stores
may be so extensive that the cells resemble adipocytes in
possessing visible lipid droplets.
CEs are also prominent in the plasma lipoproteins, wherein
approximately 70% of the cholesterol is esterified.
 Cholesterol esters make up about two third of the total
circulating cholesterol.
 Cholesterol

• product of animal metabolism

• present in various foodstuffs of animal origin such
as egg yolk, meat, and liver
• Plants contain other sterols, which are collectively
called phytosterols.
• Ergosterol (mostly in fungi) and beta- sitosterol (in
higher plants) are examples of phytosterols.
• poorly absorbed from dietary sources and therefore are
present only in small amounts in the human body.
 Biosynthesis of Cholesterol
• All nucleated cells of the body can synthesize cholesterol, including liver,
adrenal cortex, intestine, ovaries, testes, skin, arterial walls, etc., but
liver is the most important site, accounting for at least 50% of the total.
• Some sterol hormone producing endocrine tissues, such as the adrenal
cortex and the corpus luteum, have very high rates of cholesterol
synthesis.
• Endogenous cholesterol synthesis amounts to 0.5–1 g per day,
depending on the dietary supply. Low cholesterol diet enhances the
synthesis, whereas high-cholesterol diet suppresses it.
• Acetyl CoA is the source of all the 27 carbon atoms of cholesterol
• Formation of a 27-carbon molecule from a two-carbon precursor (i.e.
acetyl CoA) involves a series of condensation reactions.
• These reactions require input of a large amount of energy. The energy is
provided by the high energy thioester bonds, as also by the ATP
molecules. These reactions also require reducing equivalents, which are
provided by NADPH.
• The enzymes of the biosynthetic pathway are found in the cytosol and
the endplasmic reticulum (ER).
 Biosynthesis of Cholesterol
Stage I: Formation of 6-C Compound, Mevalonate
 Two acetyl CoA molecules condense first to form a four-carbon
compound the acetoacetyl CoA by thiolase
 One more acetyl CoA molecule condenses with the acetoacetyl CoA to
form a six carbon compound hydroxymethyl glutaryl CoA (HMG CoA) by
HMG CoA synthase
 Two types of HMG CoA synthase ( Liver parenchyma cells )
• cytosolic form - participates in cholesterol synthesis
• mitochondrial enzyme - involved in the synthesis of the ketone
bodies
 In the next step, HMG CoA is reduced by the enzyme HMG CoA
reductase to form mevalonate
 Cholesterol Synthesis
( Mevalonate Pathway)
 Cholesterol Synthesis
( Mevalonate Pathway)

 IPP and DPP -Building blocks for heme, cholesterol,Vit K,CoQ10,steroids

Cholesterol Synthesis
Cholesterol Synthesis
Cholesterol
Cholesterol vs Ketone Body Synthesis
 Regulation of Cholesterol Synthesis

• HMG CoA Reductase is inhibited by Mevalonate

and Cholesterol
• Cholesterol repress the transcription of genes for
HMG CoA Reductase
• Thru Sterol Regulatory Element Binding Protein ( SREBP)
• Insulin and Thyroxine increase the activity of HMG
CoA Reductase
• Glucagon and Glucocorticoids decrease the activity
of HMG CoA Reductase
Regulation of Cholesterol Synthesis
Regulation of Cholesterol
Synthesis
Regulation of Cholesterol
Synthesis
Regulation of Cholesterol Synthesis
LIPOPROTEIN
Lipoproteins
Structure of Lipoproteins
 Structure of Lipoproteins

 Protein part of lipoprotein is called apoprotein or

apolipoprotein.

 The apolipoproteins on surface of lipoproteins help to

solubilize the lipids and target the lipoproteins to the
correct tissues.

 The most characteristic structural feature of

apolipoproteins is the amphipathic helix, an 𝛼 -helix in
which one side is formed by hydrophobic and the other
by hydrophilic-amino acid side chains.
 Structure of Lipoproteins
 Core - contains cholesterol esters and triacylglycerols,
which, because of their non-polar nature, always avoid
contact with water
 Amphipathic coat - contains phospholipids, free cholesterol,
and proteins. It interacts with water in plasma, thereby
promoting solubility of lipoproteins.
 interactions between lipids and proteins in the lipoprotein
particle are of a purely non-covalent nature.

 Protein part of lipoprotein is called apoprotein or

apolipoprotein.

 The apolipoproteins on surface of lipoproteins help to

solubilize the lipids and target the lipoproteins to the correct
tissues.
Classes of Lipoproteins
 Separation of Lipoproteins
Electrophoresis
separates lipoproteins on the basis of their charge
and mass to yield four major bands.
Classes of Lipoproteins
Classes of Lipoproteins
Functions of Lipoproteins
Lipoprotein
Functions of Apolipoproteins
Lipoprotein
 Lipoprotein
Chylomicron
Largest lipoprotein
Synthesized in the intestine
Transport dietary triacylglycerols to skeletal muscles
and adipose tissue, and dietary cholesterol to the liver.
As the chylomicrons pass through the capillaries of
various tissues, the triacylglycerols are hydrolyzed by
the action of lipoprotein lipase (LPL), an enzyme
located on the endothelial cells.
 The fatty acids and monoacylglycerols released by the
hydrolysis diffuse directly into the tissue either for
metabolism or for storage.
Lipoprotein
Lipoprotein
Lipoprotein
Lipoprotein
 Synthesis of Lipoprotein
 Following absorption in intestine, the dietary lipids are incorporated in
chylomicrons.
 Since chylomicrons carry lipids (mainly triacylglycerols) of dietary origin,
they are synthesized and appear in circulation only after a meal rich in
fats.
 The relative content of triacylglycerols, cholesterol, phospholipids and
fat-soluble vitamins present in chylomicrons reflect the lipid
composition of the preceding meal.
 These lipid components are assembled in the SER and the Golgi
apparatus of the mucosal cells.
 Then the apolipoproteins (B-48 and A) synthesized in RER are also
incorporated. The particles so formed, called nascent chylomicrons, are
exocytosed into the laceteals of the intestinal villi.
 From these lymph vessels (i.e. laceteals) the nascent chylomicrons
reach the blood circulation via the thoracic duct.
 Lipoprotein Metabolism

But upon entering the circulation, the nascent

particles acquire apoC and apoE from plasma HDL
to form mature chylomicrons .

The acquisition of these apolipoproteins makes the

mature chylomicrons functionally competent.

In particular, the apo C-II in mature particles

activates the enzyme lipoprotein lipase (LPL).
 Lipoprotein Metabolism

 the activated LPL causes hydrolysis of about 80–

90% of the chylomicron triacylglycerols.

This is accompanied by the transfer of most of the

A- and C-apolipoproteins to HDL.

These changes convert the chylomicron into a

smaller particle, known as a chylomicron remnant.
 Lipoprotein Metabolism

Chylomicron remnant is taken up in the liver by

receptor mediated endocytosis
Uptake is mediated by ApoE via two ApoE
dependent receptors, LDL receptor and LDL
receptor and LDL receptor related protein-I (LRP-I)
Hepatic Lipase hydrolyze remnant triacylglycerol
and phospholipid
The fatty acids released from the hydrolyzed
triacylglycerols enter muscle and adipose tissue
cells, and the glycerol part enters the liver, where it
is used for synthesis of TAG.
Lipoprotein Metabolism
Lipoprotein Metabolism
Lipoprotein Metabolism
Lipoprotein Metabolism
Very Low Density Lipoproteins (VLDL)
Lipoprotein Metabolism
 Lipoprotein Metabolism

HDL Metabolism and Reverse Cholesterol Transport

Nascent HDL is synthesized and secreted from
intestine and liver
Lecithin Cholesterol Acyl Transferase (LCAT) binds
to nascent HDL
Apo A-I activates LCAT
LCAT converts Cholesterol to nonpolar cholesterol
ester
 Lipoprotein Metabolism

HDL Metabolism and Reverse Cholesterol Transport

Nonpolar core is generated forming a spherical
HDL3 with surface film of amphipathic lipids and
apolipoproteins
HDL3 accepts Cholesterol from tissues by Class B
Scavenger Receptor B-I (SR-BI) and ATP-binding
cassette transporters A1 (ABCA 1) and G-I (ABCGI)
LCAT acts on the Cholesterol in HDL3 convert it into
cholesteryl esters
Less dense HDL2 is formed
 Lipoprotein Metabolism

HDL Metabolism and Reverse Cholesterol Transport

Transport of Cholesterol between
Tissues
Cholesterol Balance in the
Tissues
Cholesterol Balance in the
Tissues
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)
DISORDERS OF LIPOPROTEIN
METABOLISM (DYSLIPOPROTEINEMIAS)