Metabolism OF CHOLESTEROL

& Ketone Bodies

By: Abdikarem darwiish
 Structure:
a. Cholesterol is an animal sterol.
b. It is solid alcohol having –OH group at C3.
c. Cholesterol occurs both as free form or in
ester form
Sources of Cholesterol:
A. Endogenous :cholesterol is formed in the
Introduction body almost in all nucleated cells from
acetyl-CoA (about 700 mg/day).
B. Exogenous: cholesterol occurs only in food
of animal origin such as egg yolk, meat,
liver and brain.
• Diet supplies about 400 mg/day
 1. Cholesterol enters in the structure of
every body cell e.g Cell membreane.
2. Cholesterol is the precursor of Vitamin
D3
3. Cholesterol is the precursor of steroid
hormones
Functions of 4. Cholesterol is the precursor of bile acids
(liver).
Cholesterol 5. Cholesterol is a major constituent of
gallstones.
• Its chief role in pathologic processes is as
a factor in the genesis of atherosclerosis
of vital arteries, causing cerebrovascular,
coronary, and peripheral vascular disease
Structure of Cholesterol
27 carbon Four fused
atoms. rings.

Only one
Peripheral
double bond
side chain.
(C=C).
 Cholesterol Structure

HO RCOO

Cholesterol(Free Cholesterol Ester(CE)

Cholesterol)
 Synthesis site

All the tissue of

the body 50% in liver 15% intestine

Remaining in skin, -Cytoplasm

adrenal cortex, -Some enzymes
reproductive tissue attached to ER.
and other parts.
 A. Location :
1. Intracellular location : Cytosol
2. Organ location
Synthesis of a. Liver is the major site of
Cholesterol cholesterol synthesis
b. Other tissues e.g intestine ,
adrenal cortex, gonads and skin
B . Precursor : acety-CoA
 Steps :

5 stages
18- acetyl CoA
36- ATP
16- NADPH
Cholesterol Synthesis

18- acetyl CoA

36- ATP
16- NADPH
 Steps:

1. Formation of acetoacetyl CoA : by condensation of two

molecules of acetyl
2. Synthesis of β-hydroxy β-methylglutaryl CoA (HMG CoA):
another molecule of acetyl CoA is added to acetoacetyl to
produce HMG CoA.
3. Formation of mevalonate : HMG CoA reductase is the rate
limiting enzyme in cholesterol biosynthesis.
• This enzyme is present in endoplasmic reticulum and catalyses the
reduction of HMG CoA to mevalonate.
4. Production of isoprenoid units: in a three-step reaction catalyzed
by kinases ,mevalonate is converted to 3-phospho 5
pyrophomevalonate which on decarboxylation forms isopentenyl
pyrophosphate (IPP).
The latter isomerizes to dimethyallyl pyrophosphate (DPP)
• 5. Synthesis of squalene : IPP and DPP condense to produce a 10-carbon
geranyl pyrophosphate (GPP).
• Another molecule of IPP condenses with GPP to form a 15-carbon farnesyl
pyrophosphate (FPP).
• Two units of farnesyl pyrophosphate unite and get reduced to produce a
30-carbon squalene .
• 6. Conversion of squalene to cholesterol: squalene undergoes
hydroxylation and cyclization utilizing O2 and NADPH and gets converted
to lanosterol.
• The formation of cholesterol from lanosterol is multistep process with a
series of about 19 enzymatic reactions.
• Reducing the carbon atoms from 30 to 27
• Removal of two methyl groups from C4 and one methyl group from C14
• Shift of double bond from C8 to C5
• Reduction in the double bond present between C24 and C25
Cholesterol
Synthesis
Summary
 Regulation-HMG CoA reductase

• Feedback control
• Hormonal control
– Inhibition by glucagon and glucocorticoids
– Activation Insulin and thyroxine
– Inhibition by drugs:the drugs compactin and
lovastatin are fungal products. They are used to
decrease the serum cholesterol level in the patients
with hypercholesterolemia.
 Cholesterol present in plasma is either free
or esterified form ( cholesteryl ester).
Total plasma cholesterol : 140-220 mg/dl
Hypercholesteremia:
I. Diet rich carbohydrates, cholesterol
and saturated fatty acids
Plasma II. Hypothyroidism: as thyroxin
stimulates conversion of cholesterol to
Cholesterol bile acids
III. Diabetes mellitus
IV. Obesity
V. Obstructive jaundice : due to
decreased excretion of cholesterol and
bile acids
 • Definition : it is decreases
plasma cholesterol concentration
below 140 mg/dl.
• Causes:
I. Prolong fasting : which causes
decreased secretion of insulin
II. Diet rich In unsaturated fatty
acids and poor in saturated
Hypocholesterolemia:- fatty acids , carbohydrates and
cholesterol
III. Liver diseases , as liver is the
site where most plasma
cholesterol is synthesized.
IV. Hyperthyroidism
V. Chronic infection as
tuberculosis
 DEGRADATION OF CHOLESTEROL

• The steroid nucleus (ring structure) of the cholesterol cannot be

metabolized in humans.
• Cholesterol (50%) is converted to bile acids, excreted in feces, serves as
a precursor for the synthesis of steroid hormones, vitamin D,
coprostanol and cholestanol. The latter two are the fecal sterols, besides
cholesterol.
I. Synthesis of bile acids
• The bile acids possess 24 carbon atoms, 2 or 3 hydroxyl groups in the
steroid nucleus and a side chain ending in carboxyl group. The bile
acids are amphipathic in nature since they possess both polar and non-
polar groups. They serve as emulsifying agents in the intestine and
actively participate in the digestion and absorption of lipids.
• The synthesis of primary bile acids takes place in the liver and involves a
series of reactions(Fig.14.29).
• The step catalysed by 7-hydroxylase is inhibited by bile acids and this is
the rate limiting reaction.
• Cholic acid and chenodeoxycholic acid are the primary bile acids and the
former is found in the largest amount in bile.
• On conjugation with glycine or taurine, conjugated bile acids (glycocholic
acid, taurocholic acid etc.) are formed which are more efficient in their
function as surfactants.
• In the bile, the conjugated bile acids exist as sodium and potassium salts
which are known as bile salts.
• In the intestine, a portion of primary bile acids undergoes deconjugation
and dehydroxylation to form secondary bile acids (deoxycholic acid and
lithocholic acid). These reactions are catalysed by bacterial enzymes in the
intestine.
• Enterohepatic circulation : The conjugated bile salts synthesized in the
liver accumulate in gall bladder.
• From there they are secreted into the small intestine where they serve as
emulsifying agents for the digestion and absorption of fats and fat-
soluble vitamins.
• A large portion of the bile salts (primary and secondary) are
reabsorbed and returned to the liver through portal vein.
• Thus, the bile salts are recycled and reused several times in a day. This is
known as enterohepatic circulation. About 15- 30 g of bile salts are
secreted into the intestine each day and reabsorbed.
• However, a small portion of about 0.5 g/day is lost in the feces. An equal
amount (0.5 g/day) is synthesized in liver to replace the lost bile salts.
• The fecal excretion of bile salts is the only route for the removal of
cholesterol from the body.
II. Synthesis of steroid hormones from cholesterol
• Cholesterol is the precursor for the synthesis of all the five classes of
steroid hormones :
(a) Glucocorticoids (e.g. cortisol)
(b) Mineralocorticoids (e.g. aldosterone)
(c) Progestins (e.g. progesterone
d) Androgens (e.g. testosterone)
(e) Estrogens (e.g. estradiol).
• A brief outline of steroid hormonal synthesis is given in Fig.14.30 and
more details are discussed under ‘Hormones
III. Synthesis of vitamin D
• 7-Dehydrocholesterol, an intermediate in the synthesis of cholesterol, is
converted to cholecalciferol (vitamin D3) by ultraviolet rays in the
 • THANKS
• ANY ENQUIRY