High-density lipoprotein metabolism: potential therapeutic targets

It is well recognized that the lowering of low-density lipoprotein (LDL) cholesterol can substantially reduce coronary artery disease (CAD)-related morbidity and mortality. The prevention and management of CAD has chiefly focused on 1 component of the lipid profile: the reduction of LDL cholesterol. Yet, the majority of patients in both the primary and secondary prevention settings continue to experience significant residual risk for acute cardiovascular events even when their LDL cholesterol is lowered aggressively with combinations of lifestyle modification and pharmacologic intervention. As a result, there is increased focus on targeting and treating low serum levels of high-density lipoprotein (HDL) cholesterol in an effort to further reduce risk for cardiovascular events, including myocardial infarction, unstable angina, ischemic stroke, and death. Epidemiologically high serum levels of HDL cholesterol are associated with reduced risk for the development of atherosclerotic disease. HDL particles are believed to be antiatherogenic secondary to their capacity to drive reverse cholesterol transport and antagonize pathways of inflammation, thrombosis, and oxidation. HDL cholesterol can be quite challenging to raise in many individuals because of the large number of polymorphisms in the genes, enzymes, cell surface receptors, and apoproteins that regulate the serum concentrations, functionality, and patterns of metabolism of HDL particles This article reviews HDL metabolism and established as well as emerging therapeutic approaches to raising serum concentrations of this fascinating and complex lipoprotein.