STUDIES ON FACTORS INFLUENCING HIGH-DENSITY LIPOPROTEIN FUNCTIONALITY AND REVERSE CHOLESTEROL TRANSPORT

Coronary artery disease (CAD) in dyslipidemic and diabetic subjects remains the leading cause of death in the Western society. Current therapeutic strategies to prevent cardiovascular diseases are primarily based on the use of statins, which inhibit key enzyme in the cholesterol synthesis, HMG-CoA reductase. Another prominent risk factor for developing premature atherosclerosis is the low levels of high-density lipoprotein cholesterol (HDL-C). Despite documented benefits of statins a good proportion of individuals still remain at a higher risk of developing CAD. Therefore, focus has shifted on HDL-raising therapeutics to further improve the CV outcome. While Niacin and fenofibrate have not shown clinical benefits in two separate trials, results from CETP inhibitors, Torcetrapib and Dalcetrapib, in phase 3 clinical studies have been disappointing despite substantial increase in HDL-C. One of the challenges encountered with measuring plasma HDL as a biomarker for cardiovascular risk is the fact that the antiinflammatory HDL becomes pro-inflammatory after it undergoes oxidative modification in diabetics. Pro-inflammatory states have also been shown to reduce HDL functionality. Thus, the lack of translatability of animal results to humans has further added challenges in the HDL therapeutics area. These findings necessitated rethinking about HDL therapeutics leading to transition in HDL therapy concept that seems to focus more around HDL functionality rather than HDL level. This PhD dissertation focuses on factors that influence HDL functionality and analyzes a correlation between HDL functionality and aortic lipid deposition. Several agents that raise HDL levels have been utilized to dissect HDL functionality. In addition, animal model of diabetes and atherosclerosis was employed to establish a correlation between HDL functionality, hyperglycemia and inflammation. Through a series of studies, it is shown that HDL function correlates with beneficial effects, and diabetes and inflammation dampens HDL functionality leading to increased accumulation of aortic lesion formation. Agents that attenuate hyperlipidemia, glycemic index and proinflammatory state improved HDL functionality leading to reductions in atherosclerotic burden.