regulation of cholesterol synthesis

regulation of cholesterol synthesis

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
reductasestep.
Following mechanisms are involved at the regulatory
step-
ÒCompetitive inhibition
ÒFeed back inhibition
ÒCovalent modification(Role of hormones)
ÒSterol mediated regulation of transcription

3. COMPETITIVE INHIBITION
Statins(Lovastatin, Mevastatin, AtorvaStatinetc.) 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
qHMG Co A reductaseis inhibited by Mevalonate
and Cholesterol.
qMevalonateis the immediate product of HMG
Co A reductasecatalyzed reaction whereas
Cholesterol is the ultimate product of the
reaction pathway.

5. COVALENT MODIFICATION (ROLE OF HORMONES)
ÒPhosphorylationdecreases the activity of the
reductase.
ÒGlucagon favors formation of the inactive
(phosphorylatedform) form, hence decreases the
rate of cholesterol synthesis
ÒIn contrast , insulin favors formation of the
active(dephosphorylated)form of HMG Co A
reductaseand results in an increase in the rate of
cholesterol synthesis
ÒCholesterol synthesis ceases when the ATP level is
low

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

7. TRANSPORT OF CHOLESTEROL
ÒCholesterol is transported in plasma in lipoproteins, and in
humans the highest proportion is found in LDL.
ÒCholesterylester in the diet is hydrolyzed to cholesterol,
which is then absorbed by the intestine together with dietary
unesterifiedcholesterol and other lipids.
ÒWith cholesterol synthesized in the intestines, it is then
incorporated into chylomicrons.
ÒNinety-five percent of the chylomicroncholesterol is
delivered to the liver in chylomicronremnants,
ÒMost 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
ÒThe normal serum cholesterol concentration
ranges between 150-220 mg/dl
ÒHigh cholesterol concentration is found in-
ÒDiabetes mellitus
ÒNephroticsyndrome
ÒObstructive jaundice
ÒFamilial hypercholesterolemia
ÒBiliarycirrhosis
ÒHypothyroidism

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. HYPOLIPIDEMICDRUGS
ÒStatins-The statinsact as competitive inhibitors of
the enzyme HMG-CoAreductase.
ÒFibratessuch as Clofibrateand gemfibrozilact mainly
to lower plasma triacylglycerolsby decreasing the
secretion of triacylglyceroland cholesterol-containing
VLDL by the liver.
ÒOmega 3 Fatty Acids (Fish Oils)-The most widely used
n-3 PUFAs for the treatment of hyperlipidemiaare the
two active molecules in fish oil: Eicosapentaenoicacid
(EPA) and Docosahexaenoicacid (DHA).

11. ROLE OF DIET IN REGULATING CHOLESTEROL
LEVELS
ÒPolyunsaturated fatty acids have a cholesterol lowering
effect
ÒThere 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 atherogeniclipoprotein.
ÒIn 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
ÒAdditional 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
ÒPremenopausal women appear to be protected against many
of these deleterious factors, and this is thought to be related
to the beneficial effects of estrogen.
ÒThere 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 apoA-I
ÒRegular exercise lowers plasma LDL but raises HDL.