Cholesterol performs essential functions in the body and is synthesized in the liver and intestines. The liver plays a central role in regulating blood cholesterol levels. Half of the body's cholesterol comes from synthesis, while the remainder comes from diet. Cholesterol is used to make bile acids, steroid hormones like cortisol and aldosterone, vitamin D, and is incorporated into cell membranes. Bile acids help emulsify fats and are recycled through enterohepatic circulation. Statins work by inhibiting HMG-CoA reductase, an enzyme involved in cholesterol synthesis but also the production of other important compounds.

1. Cholesterol and Compounds
AD

2. Cholesterol
Def:
It is a steroid alcohol of animal tissue
having 27 Carbon units, which performs
essential functions in body.
Normal Blood Cholesterol: 150-250 mg/dl

Liver has a central role in regulating blood
cholesterol level.

4. CHOLESTEROL SYNTHESIS,
TRANSPORT, AND EXCRETION


A little more than half the cholesterol of the body
arises by synthesis (about 700 mg/d), and the
remainder is provided by the average diet. The
liver accounts for 10% of total synthesis in
humans, the intestine for about another 10%.
Microsomal (endoplasmic reticulum) and cytosol
fraction of the cell is responsible for cholesterol
synthesis.

5. HMG CoA Reductase
(More Than Cholesterol Synthesis)
3Acetyl CoA (2C)
HMG CoA(6C)
HMG CoA Reductase
Mevalonate
Prenylation of
signalling peptides
(ras, rho, etc.)
Isopentenyl
adenine
(transfer RNA)
Farnesyl Pyrophosphate
Dolichols
Cholesterol
Inhibition of other key products of mevalonate may relate to
nonlipid effects & rare side effects of statins.

6. Regulation
1.
Dietary Cholesterol: Increase in Dietary
2.
Feed-back Control: Increase in Cholesterol
3.
cholesterol Causes Decrease in Denovo synthesis.
causes Inhibition of HMGCoA Reductase synthesis
(regulation of gene expression) and Inactivation of
Remaining enzymes
Liver: a) By LCAT mechanism
b) Bile acids/salts
c) Incorporation into VLDL

7. Metabolic Fates of Cholesterol
Steroid Hormones
Vitamin D
Cholesterol
Incorporation into Biological Membranes
Bile Acids

8. Types of Bile Acids/Salts

Primary bile acids

Good emulsifying agents



All OH groups on same
side
pKa = 6 (partially ionized)
Conjugated bile salts


Amide bonds with glycine
or taurine
Very good emulsifier

pKa lower than bile acids

9. Recycling of Bile Acids

Enterohepatic
circulation

98% recycling of bile
acids

10. Steroid Hormone Metabolism:
Adrenal Steroid Hormones

Aldosterone



C21 derivative of cholesterol
Promotes renal
Sodium retention


Glucocorticoids (cortisol)

Starvation




Potassium excretion
Hepatic gluconeogenesis
Muscle protein degradation
Adipose lipolysis
Adrenal androgens

Dehydroepiandroterone (DHEA)

Precurser to potent androgens in extraadrenal tissues