Published on May 20, 2012
Cholesterol : Cholesterol PowerPoint Presentation: Most abundant sterol in human body Sources : dietary (egg yolk, meat, liver etc) and biosynthesis in tissues Synthesis : - cytosol and microsomal fraction - liver is the major site of cholesterol synthesis although other tissues e.g. intestine, gonads, adrenal, skin etc. also synthesize cholesterol. - precursor : Acetyl CoA Forms : free cholesterol and esterified cholesterol PowerPoint Presentation: Cholesterol is a very hydrophobic compound. Cholesterol structure consists of - four fused hydrocarbon rings (A, B, C, and D, called the "steroid nucleus")- cyclopentano perhydrophenanthrene ring - branched hydrocarbon chain attached to C-17 of the D ring. - Ring A has a hydroxyl group at C-3, and - ring B has a double bond between C-5 and C-6 - two methyl groups C-18 & C-19 are attached to C-13 & C-10 respectively. PowerPoint Presentation: Functions of cholesterol: Maintains membrane fluidity Synthesis of Vitamin D Precursors of steroid hormones e.g. testosterone, progesterone, estrdiol , cortisol etc Formation of bile acids Biosynthesis of Cholesterol: Biosynthesis of Cholesterol Step 1—Biosynthesis of Mevalonate Step 2—Formation of Isoprenoid Units Step 3—Six Isoprenoid Units Form Squalene Step 4—Formation of Lanosterol Step 5—Formation of Cholesterol PowerPoint Presentation: Regulation of cholesterol synthesis: Synthesis of HMG- CoA reductase is inhibited by cholesterol and mevalonate HMG- CoA reductase gene(DNA) HMG- CoA reductase (mRNA) HMG- CoA reductase (protein) 2. Fed state (high fat and carbohydrates) favors while fasting inhibits cholesterol synthesis. Transcription Inhibited by cholesterol Translation Inhibited by mevalonate PowerPoint Presentation: HMG- CoA reductase dephosphorylated form phosphorylated form (active form) (inactive form) Insulin Glucagon, Glucocorticoids Thyroid hormones 4. Regulation by LDL-receptor : - liver= increased uptake of LDL- ↓ chol . Synthesis - periphery= increased uptake of LDL- ↓ chol . level Formation of Bile Acids: Formation of Bile Acids PowerPoint Presentation: Clinical Aspects: 1) Gallstone: → cholesterol – major constituent 2) Atherosclerosis & Coronary Heart disease: Hypercholesterolemia a) DM (due to high Acetyl CoA ) b) Obstructive jaundice (due to obstruction in the excretion of cholesterol) c) Hypothyroidism (↓ HDL receptors on hepatocytes ) d) Nephrotic syndrome (↑ synthesis of apoproteins ) PowerPoint Presentation: Atherosclerosis – deposition of cholesterol & cholesteryl ester in the connective tissue of arterial wall * Atherosclerosis of vital arteries cause Cerebrovascular , coronary & periferal vascular disease LDL – cholesterol – positively co-related (bad cholesterol) HDL- cholesterol – negatively correlated with (good cholesterol) cardiovascular disease. Management of Hyperlipidemia- A biochemical basis: Management of Hyperlipidemia - A biochemical basis Genetic predisposition – greatest role Dietary factors PUFAs & MUFAs – plant sources - stimulation of cholesterol excretion into intestine. - stimulation of oxidation of cholesterol to bile acids. - up regulation of LDL receptors. Saturated fAs – down regulation of LDL-Receptor Palmitate = inhibit conversion of cholesterol to bile acids. PowerPoint Presentation: - ↑ dietary fibers - Reduce total fat intake and high carbohydrates (sucrose and fructose) Life style - Lack of exercise=↑ HDL- chol . and ↓ LDL- chol . - Obesity - Male gender - Smoking, coffee drinking * Moderate alcohol intake (red wine) - ↑ synthesis of apo A-I (HDL) - antioxidants Hypolipidemic drugs: Hypolipidemic drugs Cholestyramin resin : block in reabsorption of bile acids. bile acids formation ↑↑ and LDL receptor in liver are up-regulated. 2) Sitosterol : block absorption of cholesterol from GIT 3) Statin : -competitive inhibitor of HMG CoA reductase - upregulate LDL- receptor 4) Clofibrate & gemfibrozil : divert free FAs from entering to liver to oxidation by tissues.→ decreased VLDL formation. PowerPoint Presentation: 5) Probucol : → antioxidant property= prevent accumulation of oxidized LDL → ↑ LDL catabolism by receptor independent pathway 6) Nicotinic Acid : reduces flux of FFAs by inhibiting adipose tissue lipolysis ↓ VLDL formation.