Regulation of cholesterol synthesis occurs primarily at the HMG-CoA reductase step through competitive inhibition by statins, feedback inhibition by downstream products, covalent modification by hormones like glucagon and insulin, and sterol-mediated regulation of gene transcription. Cholesterol levels are also controlled by transport in lipoproteins and uptake by tissues, and influenced by diet, lifestyle factors, and certain medical conditions that can raise or lower serum cholesterol concentration.

1. REGULATION OF
CHOLESTEROL SYNTHESIS
BY ARSH SANDHU AND AMITESHWAR SINGH

2. Regulation of cholesterol synthesis is exerted near
the beginning of the pathway, at the HMG-CoA
reductase step.
Following mechanisms are involved at the regulatory
step-
Ò Competitive inhibition
Ò Feed back inhibition
Ò Covalent modification(Role of hormones)
Ò Sterol mediated regulation of transcription

3. COMPETITIVE INHIBITION
Statins (Lovastatin, Mevastatin, Atorva Statin etc.) are the
reversible competitive inhibitors of HMG Co A reductase.
They are used to decrease plasma cholesterol levels in
patients of hypercholesterolemia.

4. FEEDBACK INHIBITION
q HMG Co A reductase is inhibited by Mevalonate
and Cholesterol.
q Mevalonate is the immediate product of HMG
Co A reductase catalyzed reaction whereas
Cholesterol is the ultimate product of the
reaction pathway.

5. COVALENT MODIFICATION (ROLE OF HORMONES)
Ò Phosphorylation decreases the activity of the
reductase.
Ò Glucagon favors formation of the inactive
(phosphorylated form) form, hence decreases the
rate of cholesterol synthesis
Ò In contrast , insulin favors formation of the
active(dephosphorylated )form of HMG Co A
reductase and results in an increase in the rate of
cholesterol synthesis
Ò Cholesterol synthesis ceases when the ATP level is
low

6. STEROL MEDIATED REGULATION OF TRANSCRIPTION
Ò The synthesis of cholesterol is also regulated by
the amount of cholesterol taken up by the cells
during lipoprotein metabolism.

7. TRANSPORT OF CHOLESTEROL
Ò Cholesterol is transported in plasma in lipoproteins, and in
humans the highest proportion is found in LDL.
Ò Cholesteryl ester in the diet is hydrolyzed to cholesterol,
which is then absorbed by the intestine together with dietary
unesterified cholesterol and other lipids.
Ò With cholesterol synthesized in the intestines, it is then
incorporated into chylomicrons.
Ò Ninety-five percent of the chylomicron cholesterol is
delivered to the liver in chylomicron remnants,
Ò Most of the cholesterol secreted by the liver in VLDL is
retained during the formation of IDL and ultimately LDL,
which is taken up by the LDL receptor in liver and extra
hepatic tissues.

8. VARIATION OF SERUM CHOLESTEROL LEVELS
Ò The normal serum cholesterol concentration
ranges between 150- 220 mg/dl
Ò High cholesterol concentration is found in-
Ò Diabetes mellitus
Ò Nephrotic syndrome
Ò Obstructive jaundice
Ò Familial hypercholesterolemia
Ò Biliary cirrhosis
Ò Hypothyroidism

9. Hypocholesterolemia- Low serum cholesterol
concentration is observed in-
Hyperthyroidism
Malnutrition
Malabsorption
Anemia
Physiologically lower levels are found in children
Persons on cholesterol lowering drugs

10. HYPOLIPIDEMIC DRUGS
Ò Statins - The statins act as competitive inhibitors of
the enzyme HMG-CoA reductase.
Ò Fibrates such as Clofibrate and gemfibrozil act mainly
to lower plasma triacylglycerols by decreasing the
secretion of triacylglycerol and cholesterol-containing
VLDL by the liver.
Ò Omega 3 Fatty Acids (Fish Oils)-The most widely used
n-3 PUFAs for the treatment of hyperlipidemia are the
two active molecules in fish oil: Eicosapentaenoic acid
(EPA) and Docosahexaenoic acid (DHA).

11. ROLE OF DIET IN REGULATING CHOLESTEROL
LEVELS
Ò Polyunsaturated fatty acids have a cholesterol lowering
effect
Ò There is the up-regulation of LDL receptors by poly- and
monounsaturated as compared with saturated fatty
acids, causing an increase in the catabolic rate of LDL,
the main atherogenic lipoprotein.
Ò In addition, saturated fatty acids cause the formation of
smaller VLDL particles that contain relatively more
cholesterol, and they are utilized by extra hepatic tissues
at a slower rate than are larger particles and thus may
be regarded as atherogenic.

12. LIFESTYLE AND THE SERUM CHOLESTEROL LEVELS
Ò Additional factors considered to play a part in coronary heart
disease include high blood pressure, smoking, male gender,
obesity (particularly abdominal obesity) and lack of exercise
Ò Premenopausal women appear to be protected against many
of these deleterious factors, and this is thought to be related
to the beneficial effects of estrogen.
Ò There is an association between moderate alcohol
consumption and a lower incidence of coronary heart
disease. This may be due to elevation of HDL concentrations
resulting from increased synthesis of apo A-I
Ò Regular exercise lowers plasma LDL but raises HDL.