CHOLESTEROL METABOLISM muhammad mustansar FJMC LAHORE

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CHOLESTEROL METABOLISM

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CHOLESTEROL METABOLISM muhammad mustansar FJMC LAHORE

  1. 1. DR MUHAMMAD MUSTANSAR
  2. 2.  Membrane component Precurser to ◦ Bile acids ◦ Vitamin D ◦ Steroid hormones
  3. 3.  Dietary cholesterol ◦ From chylomicron remnants Cholesterol from extra-hepatic tissues ◦ Reverse cholesterol transport via HDL  Chylomicron remnants  IDL De novo synthesis
  4. 4.  VLDL -> LDL ◦ Transport to extra-hepatic tissues Direct excretion into bile ◦ Gallstones commonly are precipitates of cholesterol  Occurs when bile becomes supersaturated with cholesterol  Obesity, biliary stasis, infections Bile acid synthesis and excretion into bile
  5. 5.  Primary site: liver (~1g/d) ◦ Secondary sites: adrenal cortex, ovaries, testes Overall equation:
  6. 6. O OH O − O C CH2 C CH2 C SCoA CH3 hydroxymethylglutaryl-CoAHydroxymethylglutaryl-coenzyme A (HMG-CoA)is the precursor for cholesterol synthesis.HMG-CoA is also an intermediate on the pathway forsynthesis of ketone bodies from acetyl-CoA.The enzymes for ketone body production are located inthe mitochondrial matrix.HMG-CoA destined for cholesterol synthesis is made byequivalent, but different, enzymes in the cytosol.
  7. 7. O O H3C C CH2 C SCoA H2 O + O acetoacetyl-CoA H3 C C SCoA acetyl-CoA HMG-CoA HSCoA Synthase O OH O − O C CH2 C CH2 C SCoA CH3 hydroxymethylglutaryl-CoA HMG-CoA is formed by condensation of acetyl-CoA & acetoacetyl-CoA, catalyzed by HMG-CoA Synthase. HMG-CoA Reductase catalyzes production of mevalonate from HMG-CoA.
  8. 8.  Formation of HMG CoA (cyto) ◦ Analogous to KB synthesis (mito) Conversion of HMG CoA to activated isoprenoids
  9. 9.  Condensation of isoprenoids to squalene ◦ Six isoprenoids condense to form 30-C molecue
  10. 10.  Conversion of Squalene to Cholesterol
  11. 11.  All carbons from acetyl-CoA Requires NADPH, ATP, & O 2 Stages ◦ One: forms HMG CoA ◦ Two: forms activated 5 carbon intermediates (isoprenoids) ◦ Three: six isoprenoids form squalene ◦ Four: squalene + O2 form cholesterol
  12. 12.  Cellular cholesterol content exerts transcriptional control ◦ HMG-CoA reductase  Half life = 2 hours ◦ LDL-receptor synthesis Nutrigenomics: ◦ interactions between environment and individual genes and how these interactions affect clinical outcomes
  13. 13.  Covalent Modification of HMG-CoA Reductase ◦ Insulin induces protein phosphatase ◦ Activates HMG-CoA reductase Feeding promotes cholesterol synthesis ◦ Activates reg. enzyme ◦ Provides substrate: acetyl CoA ◦ Provides NADPH
  14. 14.  Covalent Modification of HMG-CoA Reductase ◦ Glucagon stimulates adenyl cyclase producing cAMP ◦ cAMP activates protein kinase A ◦ Inactivates HMG-CoA reductase Fasting inhibits cholesterol synthesis
  15. 15.  Major excretory form of cholesterol ◦ Steroid ring is not degraded in humans ◦ Occurs in liver Bile acid/salts involved in dietary lipid digestion as emulsifiers
  16. 16.  Primary bile acids ◦ Good emulsifying agents  All OH groups on same side  pKa = 6 (partially ionized) Conjugated bile salts ◦ Amide bonds with glycine or taurine ◦ Very good emulsifier  pKa lower than bile acids
  17. 17.  Hydroxylation ◦ Cytochrome P-450/mixed function oxidase system Side chain cleavage Conjugation Secondary bile acids ◦ Intestinal bacterial modification  Deconjugation  Dehydroxylation  Deoxycholic acid  Lithocholic acid
  18. 18.  Enterohepatic circulation ◦ 98% recycling of bile acids Cholestyramine Treatment ◦ Resin binds bile acids ◦ Prevents recycling ◦ Increased uptake of LDL-C for bile acid synthesis
  19. 19. Plant stanolsNo double bond on B ringPlant sterolsDifferent side chains
  20. 20. Structures ofCommon statindrugs
  21. 21.  8 yo girl ◦ Admitted for heart/liver transplant History ◦ CHD in family ◦ 2 yo xanthomas appear on legs ◦ 4 yo xanthomas appear on elbows ◦ 7 yo admitted w/ MI symptoms  [TC] = 1240 mg/dl  [TG] = 350 mg/dl  [TC]father = 355 mg/dl  [TC]mother = 310 mg/dl ◦ 2 wks after MI had coronary bypass surgery ◦ Past year severe angina & second bypass ◦ Despite low-fat diet, cholestyramine, & lovastatin, [TC] = 1000 mg/dl
  22. 22.  Raised, waxy appearing, often yellow skin lesions (shown here on knee) ◦ Associated with hyperlipidemia Tendon xanthomas common on Achilles and hand extensor tendons
  23. 23. Xanthomas of the eyelidEruptive Xanthomas -generally associated with-generally associated with hypercholesterolemiahypertriglyceridemia
  24. 24.  Aldosterone ◦ C21 derivative of cholesterol ◦ Promotes renal  Sodium retention  Potassium excretion Glucocorticoids (cortisol) ◦ Starvation  Hepatic gluconeogenesis  Muscle protein degradation  Adipose lipolysis Adrenal androgens ◦ Dehydroepiandroterone (DHEA)  Precurser to potent androgens in extra- adrenal tissues

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