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? 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 HMG-CoA Reductase

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. See p. 261 Liver Intestine Plasma

6. HDL CM LDL HDL

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

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

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

11. 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

12. 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

13. HDL

14. C OH HO COO - H3CH3C Mevalonate R = HX = HCompactin R = CH 3 X = HLovastatin (Mevacor TM ) R = OHX = HPravastatin (Pravachol TM ) CH 3 O O CCOO - OH HO R X R = CH 3 X = CH 3 Simvastatin (Zocor TM ) STATINS (Competitive inhibitors of HMG-CoA Reductase)

15. 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