Cholesterol synthesis is regulated through feedback inhibition and transcription levels of HMG CoA reductase, the rate-limiting enzyme. Insulin increases and glucagon decreases HMG CoA reductase activity by dephosphorylation and phosphorylation respectively. Cholesterol is eliminated from the body through bile acids, bile salts, and coprostanol formed by gut bacteria. Clinical conditions related to cholesterol include atherosclerosis from excess levels, familial hypercholesterolemia due to defective LDL receptors, and familial HDL deficiency caused by a mutation preventing HDL cholesterol removal.

1. Cholesterol
Metabolism

2. Regulation
• HMG CoA reductase is the rate limiting
enzyme in cholesterol synthesis
• 1. Feed back inhibition:
• 2. Regulation at transcription
• 3. Hormones

3. Regulation at transcription
• The regulatory enzyme is HMG CoA
reductase
• Long term regulation

4. Hormonal Regulation
• The enzyme exist in phosphorylated and
dephosphorylated form.
• Insulin(dephosphorylates) increases HMG-CoA
reductase activity.
• Glucagon(phosphorylates) decreases the activity of
reductase.

5. REGULATION: BY HORMONE
DEPHOPHORYLATION
PHOSPHORYLATION

6. • Inhibition by drugs:
• Lovastatin and other statin group of drugs

7. Fates of Cholesterol
• It is exported in one of the three forms: Biliary
cholesterol, bile acids or cholesteryl ester.
• About 1 g of cholesterol is eliminated from the body
per day.

8. • Coprostanol is the principal sterol in the feces;
it is formed from cholesterol by the bacteria in
the lower intestine.
• Enterohepatic circulation

9. • A small fraction of bile salt is eliminated in the
feces.
• It represent a major pathway for the
elimination of cholesterol
• Bile acid sequestrants are used in treatment of
hypercholesterolemia

10. Bile acids are formed from
Cholesterol
• Primary bile acids are synthesized in the liver
from cholesterol.

12. Formation of Cholesteryl esters
• Cholesteryl esters are formed in the liver through the
action of ACAT

14. Steroid hormones are formed by side chain
cleavage
• Humans derive all their steroid hormones from
cholesterol.
• Two classes of steroid hormones are synthesized:
• Sex hormones are produced in male and female
gonads and the placenta.

16. Intermediates in cholesterol Biosynthesis have
many alternative fates.

17. CLINICAL ASPECTS
• ATHEROSCLEROSIS
• Excess cholesterol accumulates in blood
vessels forming plaques.
• Has high cholesterol levels.

18. • FAMILIAL HYPERCHOLESTEROLEMIA
• Defective LDL receptor and thus lack receptor-
mediated cholesterol uptake by LDL.
• Extracellular cholesterol do not enter cell to
regulate cholesterol biosynthesis .
• Thus endogenous cholesterol synthesis
continues despite of increased extracellular
levels.
CLINICAL ASPECTS

19. • FAMILIAL HYPERCHOLESTEROLEMIA
• Statin drugs are the structural analogues of
HMG CoA ,
• Used to control plasma cholesterol level in
hypercholesterolemic patients.
CLINICAL ASPECTS

20. • FAMILIAL HDL DEFICIENCY
• HDL levels is low,
• mutation of ABC1 protein,
• HDL cannot take up cholesterol from cell
lacking ABC1 protein and are destroyed.
CLINICAL ASPECTS

21. • Cholelithiasis:
• Cholesterol precipitates in the gall bladder,
initiating the occurrence of cholelithiasis