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Cholesterol Metabolism

Cholesterol Metabolism. Southwestern Medical School Dallas, Texas. Familial Hypercholesterolemia. 1 in a million homozygous HO (both alleles) 1 in 500 heterozygous HT (one defective allele) HO serum cholesterol 650-1000 mg/100 ml HT serum cholesterol 250-500 mg/100 ml

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Cholesterol Metabolism

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  1. Cholesterol Metabolism Southwestern Medical School Dallas, Texas

  2. Familial Hypercholesterolemia • 1 in a million homozygous HO (both alleles) • 1 in 500 heterozygous HT (one defective allele) • HO serum cholesterol 650-1000 mg/100 ml • HT serum cholesterol 250-500 mg/100 ml • HO develop atherosclerosis, die before 20 yrs • HO death due to heart disease • HT enjoy normal life span but are at risk

  3. What’s Wrong in FH? HMG-CoA Reductase • Suppressed by cholesterol • 50-100 fold more active without cholesterol • FH have high activity all the time • Purified HMG-CoA reductase is inhibited • Cholesterol not entering cell to suppress • Receptor for cholesterol not present • FH must lack a means of taking up the cholesterol from the plasma

  4. What did Goldstein and Brown Accomplish? • LDL has a specific membrane surface receptor • LDL receptors are needed to take up cholesterol • The binding of LDL to a receptor initiates endocytosis, which brings LDL and its receptor inside the cell within an endosome • The endosome fuses with a lysosome • LDL receptor escapes degradation • Cholesterol is free inside the cell • Receptor recycles to the cell surface

  5. Intestine Liver Liver Plasma See p. 261

  6. HDL CM LDL HDL HDL HDL

  7. Cholesterol Uptake from LDL See p 263 Golgi Coated vesicle ACAT Endosome Coated Pit Lysosome LDL with apoB100

  8. Membrane-like coat ApoB100 LDL (180-260) Angstroms Core of cholesterol esters LDL Particles Cholesterol-rich, triglyceride-poor lipoprotein particles

  9. Clathrin Coat surrounding coated pits Coated Pits shown with actin filaments

  10. Lipoprotein Metabolism I • Liver and intestine are primary source of circulating lipids • Chylomicrons carry triacylglycerols and cholesterol esters from intestine to tissues • VLDL carry same from liver • Lipoprotein lipases hydrolyze triacylglycerols • VLDL IDL  LDL • LDL with apoB100 enters tissues

  11. Lipoprotein Metabolism II • HDL smallest LP • Made in liver, released with no cholesterol • Life span 5-6 days (longest LP) • Receives cholesterol esters from LCAT • Cholesterol ester transfer protein transfers ester to LDL and VLDL • Most cholesterol esters are returned to liver

  12. HDL

  13. HO C COO- X O OH HO O CH3 C COO- H3C CH3 OH R Mevalonate STATINS (Competitive inhibitors of HMG-CoA Reductase) R = H X = H Compactin R = CH3 X = H Lovastatin (MevacorTM) R = OH X = H Pravastatin (PravacholTM) R = CH3 X = CH3 Simvastatin (ZocorTM)

  14. Summary • LDL is required for cholesterol absorption • LDL arises from VLDL by TG removal • Lipoprotein lipase required to form LDL • LDL has apoB100 to recognize receptor • Receptor-mediated endocytosis • HDL takes cholesterol from LDLvia LCAT • HDL cholesterol goes back to the liver for oxidation, not deposition

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