regulation of cholesterol synthesis

regulation of cholesterol synthesis

• 1.
  REGULATION OF CHOLESTEROL SYNTHESIS BYARSH SANDHU AND AMITESHWAR SINGH
• 2.
  Regulation of cholesterolsynthesis 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 HMGCo 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 (ROLEOF 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 REGULATIONOF 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 ÒCholesterol 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 SERUMCHOLESTEROL 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 serumcholesterol 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 DIETIN 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 THESERUM 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.