HDL in atherosclerosis: actor or bystander?

Despite dramatic improvement in treatments for reducing risk for coronary heart disease (CHD), it is still the leading cause of mortality in the developed world. In the past decade, a major improvement in reducing low-density lipoprotein (LDL) cholesterol has been achieved with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This approach has been shown to be beneficial in both primary and secondary prevention of CHD. On the other hand, while a reduced high-density lipoprotein (HDL) cholesterol level is an independent CHD risk factor, no HDL cholesterol goal has yet been established. The Helsinki Heart Study and the Veterans Affairs High-density Lipoprotein Intervention Trial documented that increasing HDL cholesterol with gemfibrozil significantly decreases coronary events or stroke in CHD patients either with elevated non-HDL cholesterol or normal LDL cholesterol levels plus low HDL cholesterol. Investigations with statins have focused on their efficacy not only in significantly decreasing total cholesterol, LDL cholesterol, and triglyceride levels but also in increasing HDL cholesterol concentrations. The two different classes of drugs (statins and fibrates) have different effects on the various HDL subspecies. As new members of these drug classes and other novel drugs are emerging, there is interest in clarifying whether HDL is only a bystander (an indicator for other CHD risk factors) or it has an active role in the development of CHD. If HDL has an active role, there is a need to determine if any HDL subspecies are protective. It is now clear that HDL plays a pivotal role in cellular cholesterol efflux via the interaction of apolipoprotein A-I with the ATP binding cassette transporter A-1. Thereafter the cholesterol is esterified by lecithin:cholesterol acyltransferase; HDL is remodeled by cholesterol ester transfer protein (CETP) and hepatic lipase. The cholesterol in HDL can either be transferred to apolipoprotein B-containing particles via CETP or delivered directly to the liver with the help of scavenger receptor B1.