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  1. CHOLESTEROL METABOLISM M.Prasad Naidu MSc Medical Biochemistry, Ph.D.Research Scholar

  2. Cholesterol Metabolism • Sources of cholesterol • Cholesterol synthesis • Long and short term regulation • SREBP-2 • Lowering cholesterol • Calculating your risk for CHD

  3. Roles of Cholesterol • Membrane component • Steroid synthesis • Bile acid/salt precursor • Vitamin D precursor

  4. Sources of Cholesterol Cholesterol synthesized in extrahepatic tissues De novo synthesis Diet Liver cholesterol pool Secretion of HDL and VLDL Free cholesterol In bile Conversion to bile salts/acids

  5. Cholesterol Structure FA for esterification

  6. Dietary Cholesterol • Animal products – eggs • Absorb about 50% • Increase intake = decreased absorption • Excrete – 1 g/day (bile acids)

  7. Dietary Cholesterol • Assume 400 mg intake / day • 200 mg is absorbed • 1000 mg is excreted • 800 mg from de novo synthesis Lowering cholesterol in diet has very little effect on blood cholesterol !!!

  8. Cholesterol Synthesis Similar to ketogenic pathway Occurs in cytosol Requires NADPH and ATP Highly regulated 80 % in liver, ~10% intestine, ~5% skin


  10. HMG CoA Reductase : Regulation • Short-term regulation • Inhibited by phosphorylation • AMP-dependent protein kinase • When AMP is high (or ATP low!), why waste energy on cholesterol synthesis • Long-term regulation • Proteolysis • Degradation stimulated by cholesterol and cholesterol metabolites • Sterol-sensing domain

  11. HMG CoA reductase - Phosphorylation HMG CoA reductase – OH (active) HMG CoA reductase – P (inactive) AMP-Activated Protein Kinase (high activity) (+) AMP phosphatase kinase (+) (+) AMP-Activated Protein Kinase (low activity) increase cAMP insulin Glucagon/epi

  12. HMG CoA Reductase : Regulation • Transcriptional regulation • SREBP-2 • Responds to cellular levels of sterols

  13. SREBP cleavage activating protein

  14. Site 1 and site 2 protease -

  15. LP LDL receptor Negative Feedback (-) synthesis Free Cholesterol Pool Negative Feedback (-) acat Steroid synthesis CE C HDL

  16. Lowering Cholesterol • Statins – decrease HMG CoA reductase activity • Muscle weakness • Why?

  17. NH3+ NH3+ Lowering Cholesterol • Bile sequestering agents liver Bile acids Bile acids 95 % reabsorbed • Bind bile acid • Utilize more cholesterol • to make bile acids >10% in feces 5% in feces

  18. Lowering Cholesterol • Oat bran • Soluble fiber • Bind bile acids? • Niacin • 3-8 grams / day (need 60 mg) • Inhibits VLDL excretion ? (fatty liver) • Flushing and liver damage


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