Apolipoprotein A-I and cholesterol efflux: the good, the bad, and the modified.

Abstract

High-density lipoprotein (HDL) cholesterol is strongly and inversely associated with coronary heart disease. However, recent developments have raised major questions about the causal nature of this relationship. Several randomized controlled clinical trials of HDL-raising interventions have failed to demonstrate reduction in risk of major adverse cardiac events.1–4 Furthermore, in 1 Mendelian randomization study, genetic variants associated with increased HDL cholesterol were not associated with protection from coronary heart disease.5 It has been proposed that HDL can be dysfunctional and that this might cloud the relationship between HDL cholesterol and coronary heart disease. In this issue of Circulation Research , Shao et al6 further our understanding of the concept of HDL dysfunction by showing that oxidative modifications of apoA-I, the main protein constituent of HDL, impair its ability to accept cholesterol from macrophages. Article, see p 1733 HDL may protect against atherogenesis via several potential mechanisms. HDL has been shown to inhibit inflammation,7 regulate nitric oxide production,8 function in innate immunity,9 and, in its most extensively studied property, remove excess cholesterol from macrophages in the process of reverse cholesterol transport. During cholesterol efflux, lipid-poor apoA-I and mature HDL interact with integral membrane proteins ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, respectively, to accept cholesterol from cells.10 Our group and others have shown that the cholesterol efflux capacity of HDL inversely correlates with atherosclerotic vascular disease.6,11,12 The addition of niacin to statin therapy failed to improve cardiovascular outcomes but also did not improve HDL cholesterol efflux capacity,13 providing a …