HDL-Cholesterol

1. HDL-Cholesterol By Ashraf Reda MD Professor of Cardiology Head of Cardiology Department Menofia University

2. Structureof HDL ----- Surface Monolayer of Phospholipids and Free Cholesterol apoA-I apoA-II Hydrophobic Core of Triglyceride and Cholesteryl Esters Rye KA et al. Atherosclerosis 1999;145:227-238.

3. Structure of high-density lipoprotein (A)

4. Reverse cholesterol transport Peripheral Tissue Blood Excess cholesterol Liver Bile

5. Reverse cholesterol transport and HDL metabolism Bile FC A-1 A-1 CE CE FC ABC1 LCAT SR-B1 CE FC Nascent HDL from liver or intestine Mature HDL Macrophage CE= cholesterol ester; FC= free cholesterol; A-1= apolipoproteinA-1; ABC1= ATP-binding cassettte protein-1; LCAT= Lecithin:cholesterol acyl transeferase; SR-B1=scavenger receptor class B1

6. HDL metabolism: Reverse cholesterol transport and the role of CETP Bile FC A-1 A-1 CE CE FC ABC1 FC LCAT SR-B1 CE Nascent HDL from liver or intestine Mature HDL Macrophage CETP LDL receptor SR-A B Oxidation CE VLDL/LDL

7. Genes involved in HDL metabolism • HDL assosciated Apos.: • Apo-A1 • Apo-E • Apo-IV • Modifying plasma enzymes and transfer protein • LCAT- CETP- PLTP • LPL- HL- Endoth. lipase • Cellular and cell surface protein • ABC1 • SR-B1

8. Primary (genetic) causes of low HDL • Apo-A1: • Complete Deficiency • Mutation (Milano Apo-A1) • LCAT • Complete deficiency • Partial (fish eye disease) • ABC-1 • Tangier disease (homo- or hetero- zygos) • Familial hypo alpha lipoproteinemia • Unknown genetic A/E • Metabolic syndrome • FCH with low HDL • Hypoalphalipoproteinemia HDL A-1 CE Mature HDL A-1 FC ABC-1 FC Macrophage

9. HDL • Reverse cholesterol transport(Apo-A1—ABC-A1) • Inhibition of adhesion molecules • Antioxident • Vasotonic effect • Prevent LDL oxidation and deposition

10. Novel therapeutic modalities • Milano type-apo A1 acutely increase HDL • CETP inhibitors • Over expression of LCAT

11. Secondary causes of increased HDL: • Extensive regular aerobics • High fat diet • Regular substantial alcohol intake • Estrogen replacement therapy • Drugs • Phenytoin

12. HDL-raising effect of exercise the Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study

13. Drugs • Fibrates • Niacin • Statins • CB1 receptor blockers

15. VA-HIT LRIAL Gemfibrozil 1200mg TG 31% No LDL change HDL 6% Risk reduction MI+CHD death +Stroke 24% P<0.001

16. Blocking the over-activated endocannbinoid system CB1 blockade Central CB1 Blockade Perepheral CB1 blockade (Adipose tissue) Food intake Exess abdominal fat Adeponectin Insulin Resistence Alter the atherogenic lipid profile CRP

17. HDL cholesterol and triglyceride parameters in the rimonabant- and placebo-treated groups Scheen A. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA.

18. RIO-LIPIDS: Changes from baseline for the end points in the intention-to-treat population *last-observation-carried-forward analysis Després JP et al. N Engl J Med 2005; 353: 2121-2134.

19. CB1 Lipoprotein lipase activity Adipose tissue --- TNF-a Adiponectin Fat accumulation in adipose T --- Adeponectin ---- + + ---- FA oxidation Glucose uptake FFA clearance Insulin sensetivity Muscle

20. PROactivesubgroup analysis: Outcomes in patients with type 2 diabetes and previous MI TG 11% HDL 18% Erdmann E. American Heart Association Scientific Sessions 2005; Nov 13-16, 2005; Dallas, TX.

21. Statins are still the first line and LDL less than 70-100 mg/dl is the primary target

22. ADA recommendation:

23. Conclusions

24. HDL: mechanisms of benefit • Reverse cholesterol transport • Protections against LDL oxidation • Anti-inflamatory

25. HDL raising strategies • Exercise, LSM and better diabetes control; • PPAR agonists and metformin treatment; • Fibrates, Niacin and CB1-RB • Statins • CETP inhibitors, LCAT expression • Gene manipulations: Apo A, ABC1

26. Thank you