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Cholesterol Metabolism

Cholesterol Metabolism. Sources of cholesterol Cholesterol synthesis Long and short term regulation SREBP-2 Lowering cholesterol Calculating your risk for CHD. Roles of Cholesterol. Membrane component Steroid synthesis Bile acid/salt precursor Vitamin D precursor.

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Cholesterol Metabolism

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

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

  3. 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

  4. Cholesterol Structure FA for esterification

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

  6. 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 !!!

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

  8. Cholesterol Synthesis

  9. 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

  10. 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

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

  12. SREBP cleavage activating protein

  13. Site 1 and site 2 protease -

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

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

  16. 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

  17. 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

  18. Unsaturated fats and Cholesterol

  19. Calculate your risk

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