Cholesterol Synthesis, Endocytosis and Hyperlipidemia June 7, 2004 (153C) Peter A. Edwards (Department of Biological Che

1. Cholesterol Synthesis, Endocytosis and Hyperlipidemia June 7, 2004 (153C) Peter A. Edwards (Department of Biological Chemistry)

2. Cholesterol (mg/dl) Triglycerides (mg/dl) Total LDL HDL Desirable Borderline High risk <200 200-239 >240 <100 ~129 >160 >60 <40 <150 150-199 >200 Hyperlipidemia Hyperlipidemia is linked to: atherosclerosis, MI/heart attack (50% fatal), diabetes. Metabolic Syndrome often associated with TGs>150 mg/dl. NIH guidelines for treatment for high cholesterol and/or triglycerides are at (http://www.nhlbi.nih.gov/guidelines/cholesterol/atglance.htm).

3. Plasma Lipoproteins; lipid transporters Chylomicrons (lipid absorption) LDL (Metabolic syndrome) VLDL HDL (protective;females>males)

4. epitope An epitope on apoB interacts with the LDL receptor on the cell surface. Each LDL contains 1500 molecules of cholesteryl esters.

5. Development of Atherosclerosis Accelerated by high levels of LDL or low levels of HDL

6. Lumen Plaque shoulder; site of rupture

7. Angiography identifies lesions/ plaques. Lesion/plaque (lesions<80% occlusion are often asymptomatic)

8. HDL cholesterol HDL

9. Lipid Absorption; dietary fat is transported to the liver by chylomicrons TGs in chylomicron core Fatty acids + glycerol (adipose tissue and muscle) Lipid hydrolysis and absorption TG-rich core

10. Lipoprotein Metabolism hepatic lipids are secreted as VLDL and subsequently converted to LDL TGs in VLDL core Fatty acids + glycerol CE-rich cholesterol secretion TG-rich HDL HDL

11. The LDL receptor and mutated LDL receptors (Familial Hypercholesterolemia)

12. Endocytosis and cholesterol delivery; the LDL receptor proton pump (acidification) pH~6 pH<5 (signal)

13. How important is the LDL receptor in controlling plasma LDL levels? Familial Hypercholesterolemia Autosomal dominant disease. Mutations in the LDL receptor gene result in elevated plasma LDL levels Cholesterol (mg/dl) FrequencyLDL total Normals 100-150 <200 Heterozygote FH 1/500 persons ~300-450 300-500 Homozygote FH 1/1,000,000: ~450-1100 500-1200 Afrikaner FH (heteroz) 1/50 French Canadians >1/500 (heterozygotes)

15. Endocytosis and cholesterol delivery; the LDL receptor proton pump (acidification) pH~6 pH<5 (signal)

16. Cholesterol/isoprenoid synthesis and metabolism

17. Statins; competitive inhibitors of HMG-CoA reductase activity. Statins are structurally related to HMG-CoA, the substrate of HMG-CoA reductase.

18. Statins inhibit hepatic HMG-CoA reductase activity. The decrease in cholesterol synthesis and cholesterol levels in the cell result in increased expression of the LDL receptor and HMG-CoA reductase. Statins

19. Statins inhibit hepatic HMG-CoA reductase/cholesterol synthesis and increase LDL receptor expression.

20. Effect of Statin treatment on plasma cholesterol (LDL) (Heterozygous FH)

21. Cellular cholesterol concentrations control nuclear SREBP levels and transcription of LDL receptor and other SREBP-target genes (Statin treatment) High expression of the LDL receptor; results in increased clearance of plasma LDL into the liver (high fat diet) Low expression of the LDL receptor gene; results in decreased clearance of plasma LDL

22. Patients with the homozygous form of Familial Hypercholesterolemia (FH) have mutations in both LDL receptor genes. They have very high LDL levels (500-1100 mg/dl) and may have heart attacks before they are 10 years old. They die at an early age of atherosclerosis. Will the LDL levels of these FH patients decrease if they are given Statins? How would you treat them to lower their plasma LDL levels in order to reduce their chances of having a heart attack?

24. Plasma cholesterol reduction in a patient with homozygous Familial Hypercholesterolemia (gene therapy!)

25. Summary: Lipoprotein metabolism

26. HDL cholesterol HDL

27. Treatments for Hyperlipidemia 1.) Altered life style; diet and exercise; stop smoking; control diabetes. 2.) Exercise; can raise HDL and lower LDL levels. 3.) Drugs: a) HMG-CoA reductase inhibitors (Statins); lower LDL cholesterol levels 25- 50%. b) Bile acid sequestrants; lower LDL levels. c) Niacin (Nicotinic acid); decreases VLDL secretion (lowers TGs) and increases HDL. d) Fibrates (PPARa agonists) lower plasma TGs. e) Aspirin: Anti-thrombolitic (reduces blood clotting). f) Thrombolytic therapy. eg. treatment with tissue plasminogen activator (tPA) to dissolve the blood clot/thrombi at the site of the infarct. 4.) Surgery includes: i. By-pass surgery. ii. Angioplasty (balloon) +/- stents. After surgery, patients are routinely put on Statins (to lower LDL cholesterol), aspirin (to reduce thrombi), beta blockers and ACE inhibitors (to reduce blood pressure and heart contraction). iii. Heart transplant (for patients with heart failure).

28. Primary Lipid Disorders Familial defective apoB FH (high LDL) Abetalipoprotein- emia (LPL deficiency) (LPL deficiency) (high TGs)

29. MUTANT epitope An epitope on apoB normally interacts with the LDL receptor. A mutation at this site impairs LDL clearance from the plasma.

30. Clathrin

31. Endocytosis and cholesterol delivery; the LDL receptor Wolmans disease (Acid lipase defect)