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Cholesterol
Cholesterol biosynthesis is a multi-step process that begins with acetyl-CoA and occurs primarily in the liver and other tissues. Key steps include the conversion of HMG-CoA to mevalonate by the rate-limiting enzyme HMG-CoA reductase. Cholesterol can then be used for membrane structure, steroid hormone synthesis, or converted to bile acids which are secreted in the bile. Cholesterol levels are regulated by feedback inhibition of HMG-CoA reductase and uptake/secretion of cholesterol and bile acids. Statins lower cholesterol by inhibiting HMG-CoA reductase.
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Cholesterol
- 1. CHOLESTEROL BIOSYNTHESIS • Containscyclopentano perhydro phenanthrene ring. • Contains 27 c atoms • Contains one hydroxyl group at 3 – c atom • OH group is hydrophilic in nature
- 3. Cholesterol synthesis • Biosynthesistakes place in • Liver makes 80% of endogenous cholesterol • Adrenal cortex • Testis • Ovaries • Intestine • Enzymes are partly in ER and partly in Cytoplasm • Rate limiting enzyme is HMG COA reductase
- 4. Cholesterol synthesis • Totaldaily cholesterol production is 1 g/d • Recommendation is 300 mg/d intake • Actual is 600 mg/d of which only 300 mg/d is absorbed • synthesis is at least 2/3 of total
- 5. MITOCHONDRION Fatty acids (2) AcetylCoA β-oxidation Acetoacetyl CoA HMG CoA HMG CoA synthase Thiolase Acetoacetate β-Hydroxybutyrate Ketone bodies (only synthesized in liver) HMG CoA lyase oxaloacetate Citrate Citrate Mevalonate CHOLESTEROL smooth endoplasmic reticulum HMG CoA reductase Acetoacetyl CoA HMG CoA cytoplasm HMG-CoA synthase Thiolase Figure 1. Synthesis of HMG-CoA in mitochondria (ketone bodies) and cytoplasm (cholesterol) Lyase (requires ATP) OAAmalatepyruvate+NADPH malic enzyme (2) Acetyl CoA Statins
- 6. Mevalonate Active Isoprenoids (C5) Squalene(C30) 3ATP CO2 Several Condensation Steps 3ADP NADPH NADP+ Stage 2 Squalene (C30) Cyclization Squalene epoxidase/ cyclase Lanosterol (C30) (4-ring structure) O2 NADPH NADP+ Stage 3 Stage 4 Lanosterol (C30) (19 steps)O2 NADPH NADP+ 3 CH3 Cholesterol (C27) Acetyl CoA (C2) HMG-CoA HMG-CoA Reductase Mevalonate (C6) NADPH NADP+ Stage 1 Figure 2. The four stages of cholesterol biosynthesis rate-determining step cholesterol activates proteolytic degradation amount controlled by induction/repression hormonally controlled via phosphorylation
- 7. Cholesterol synthesis 26steps 3 stages 3 mol of acetyl CoA are used to synthesize 3-hydroxy-3-methylglutaryl CoA (HMG CoA) HMG CoA to squalene Rate limiting step of HMG CoA to mevalonic acid by HMG CoA reductase Formation of cholesterol from squalene
- 8. Cholesterol homeostasis Intestine Diet Excretion LiverPlasma Tissues Normal cholesterol level in adults: < 200 mg/dL
- 9. cholesterol abundance inthe cell: • Most excess cholesterol is converted to cholesterol esters by ACAT (acyl-CoA: cholesterol acyltransferase). • Some excess cholesterol is transferred to endoplasmic reticulum (ER)
- 10. Regulation of Cholesterol biosynthesis •Negative feedback of cholesterol on activity of HMG CoA reductase • The amount of dietary intake determines the cholesterol biosynthesis • Short term regulation: » Covalent modification - dephosphorlytated HMG COA reductase is active • Long term regulation: suppression of transcription of the gene Hormones: Insulin activates HMG COA reductase Glucagon inactivates HMG COA reductase
- 11. Degradation of HMG-CoA reductaseis regulated by cholesterol levels ER membrane Low cholesterol HMG-CoA Red stable High cholesterol HMG-CoA Red degraded
- 12. HMG-CoA reductase activitycan be regulated in response to AMP- dependent protein kinase P Active Less active
- 13. Cholesterol catabolism • Cholesterolis NOT an energy-producing nutrient • Transported to liver and excreted as bile • 55% as cholesterol, 45% as bile acids
- 14. FATES OF CHOLESTEROL Membranestructure Precursor of steroid hormones and vitamin D Esterification for storage Esterification for elimination Precursor to bile salts
- 15. Figure 4. CholesterolMetabolism - Bile Acid Synthesis and its Regulation Cholesterol (1st ring only) HO Feed forward induction by cholesterol via binding to liver LXR receptor Feedback repression by bile acids via binding to liver FXR receptor O2 + NADPH vitamin C (cofactor) NADP+ 7α-Hydroxycholesterol Bile Acids: Cholic acid Chenodeoxycholic acidmultipl e steps 7α-Hydroxylase feedback repression broken by cholestyramine SYNTHESIS OF BILE SALTS
- 16. SUMMARY OF FACTORSAFFECTING CHOLESTEROL BALANCE Decrease in intracellular free cholesterol is the result of: esterification of cholesterol by ACAT for storage use of cholesterol as precursor to other steroids or bile acids Increase in intracellular free cholesterol is the result of: endocytotic uptake of cholesterol-containing lipoproteins by the LDL receptor cholesterol biosynthesis cholesterol ester hydrolysis by cholesterol esterase
- 17. HMG-CoA reductase isthe target of “statins”, drugs commonly taken to reduce cholesterol Statins: Lovastatin (Mevacor) Simvastatin (Zocor) Prevastatin (Pravachol) Atorvastatin (Lipitor)
- 18. Hot off thepress: a new cholesterol lowering drug Devlin Fig. 17.38 cholesterol (C-esters) Etezimibe (Zetia) For use in conjunction with statins
- 19. REVIEW OF CHOLESTEROL 1.Whatis the name of the steroid ring present in cholesterol ? 2.What is the rate limiting enzyme? 3.Where the cholesterol biosynthesis takes place? 4.In which cellullar organelle the cholesterol biosynthesis takes place? 5.What are the products form from cholesterol? 6.What are bile salts? 7.What is the rate limiting enzyme in bile acid synthesis? 8.What are the functions of cholesterol? 9.Which vitamin is synthesised from cholesterol? 10.How statin drugs reduces cholesterol level? 11. What is the normal level of cholesterol? SHORT NOTES: 1.Write the fate of cholesterol? 2.What are bile acids and mention its function? ESSAY: 1.Describe in detail about the biosynthesis of cholesterol and its degradation products Mention its clinical significance.