Regulation of Cholesterol Synthesis

Apo A1, the major apoprotein in HDL activates LCAT(Lecithin cholesterol acyltransferase).The discoid HDL whoich has mainly ApoA1 receives cholesterol from the peripheral tissues which is estrified by LCAT.Esterification makes the cholesterol hydrophobic and is pushed to the core of HDL.As more and more cholesterol is taken up and esterified,the HDL becomes spherical.

LDL contains cholesterol as the main lipid component. A positive correlation exists between the incidence of atherosclerosis and the plasma concentration of LDL cholesterol.

The LDL (apoB-100, E) receptor is defective in familial hypercholesterolemia, a genetic condition which blood LDL cholesterol levels are increased, causing premature atherosclerosis.

B i.e. LDL

C i.e. HMG-Co-A Synthase

D i.e. Palmitic acid; E i.e. Stearic acid

Both cholesterol and ketone bodies are synthesize from (3) beta hydroxyl (3) beta methyl glutary CoA (ie HMG CoA). So enzymes, thiolase & HMG CoA synthase involved in conversion of acetyl CoA to HMG CoA are common to synthesis of cholesterol and ketone bodies bothQ. However, cytoplasmic HMG CoA synthase is involved in cholesterol synthesis, whereas mitochondrial HMG CoA synthase is involved in Ketone body synthesis.

Cholesterol synthesis is controlled by regulation of HMG COA reductase, which is a rate limiting enzymeQ.

Cholesterol, the major sterol in animal tissue has steroid nucleusQ. Of the cholesterol absorbed, 80-90% is esterified with long chain fatty acids (mostly saturated) such as palmitic and steric acidsQ. Whereas, substitution of saturated FAs by poly unsaturated FAs in diet has beneficial effects and lowers cholesterol.

Cholesteryl ester is tranfered from HDL to VLDL and chylomicrons in exchange with triglyceride by the cholesteryl ester transfer protein (CETP).

Ans. is ‘a’ i.e., HMG Co A reductase

Ans. is’b’  i.e., Nicotinic acid

Nicotinic acid (Niacin)

• There are three main type of lipases related to metabolism of lipoproteins ‑

1. Lipoprotein lipase→ Present in blood vessels and causes hydrolysis of tryglyceride content of VLDL and chylomicrones.
2. Hepatic lipase → Converts IDL to LDL by hydrolysing the triglyceride content of IDL.
3. Hormone sensitive lipase → Present intracellularly in peripheral tissue and causes intracellular lipolysis by hydrolysing triglycerides.

• Niacin (Nicotinic acid) inhibits intracellular lipolysis by inhibiting hormone sensitive lipase→ intracellular FFA to liver→ triglyceride synthesis.
• Niacin also increases the activity of lipoprotein lipase→ T hydrolysis of VLDL triglyceride.
• Nicotinic acid also reduces the production of VLDL in liver by inhibiting TG-synthesis → indirectly the VLDL degradation products IDL and LDL are also reduced.
• Nicotinic acid is the most effective drug to raise HDL-CH.
• Increased HDL is due to interference of direct pathway of HDL cholesterol to liver which involves apo-A,→ Niacin decreases apo-A, mediated hepatic clearance.
• Nicotinic acid is used in type I, III, IV & V hyperlipoproteinemias.

Ans. is ‘d’ i.e., Lovastatin 

• Statins (Lovastatin) competitively inhibit the conversion of HMG-CoA to mevalonate (rate limiting step in cholesterol synthesis) by inhibiting the enzyme HMG-CoA reductase.

Hvpolipidemic drugs

1. HMG-CoA reductase inhibitors (statins) – Lovastatin, Simvastatin, Pravastatin, Atorvastatin, Rosuvastatin.
2. Bile acid sequestrants (Resins) – cholestyramine, colestipol.
3. Activate lipoprotein lipase (fabric acid derivatives) – clofibrate, gemfibrozil, bezafibrate, fenofibrate. 4.Inhibit lipolysis and triglyceride synthesis – Nicotinic acid.
4. Other – Probucol, Gugulipid, Ezetimibe, Avasimibe, Torcetrapib.

• Ezetimibe inhibits intestinal cholesterole absorption.
• Avasimibe inhibits enzyme acyl Coenzyme A : cholesterol acyl transferase-1 (A CAT-1) which causes esterification of cholesterol.
• Torcetrapib inhibits cholesterol ester triglyceride transport protein -4 T HDL cholesterol.