High-density lipoproteins, reverse cholesterol transport and atherogenesis

Plasma HDL-cholesterol concentrations correlate negatively with the risk of atherosclerotic cardiovascular disease (ASCVD). According to a widely cited model, HDL elicits its atheroprotective effect through its role in reverse cholesterol transport, which comprises the efflux of cholesterol from macrophages to early forms of HDL, followed by the conversion of free cholesterol (FCh) contained in HDL into cholesteryl esters, which are hepatically extracted from the plasma by HDL receptors and transferred to the bile for intestinal excretion. Given that increasing plasma HDL-cholesterol levels by genetic approaches does not reduce the risk of ASCVD, the focus of research has shifted to HDL function, especially in the context of macrophage cholesterol efflux. In support of the reverse cholesterol transport model, several large studies have revealed an inverse correlation between macrophage cholesterol efflux to plasma HDL and ASCVD. However, other studies have cast doubt on the underlying reverse cholesterol transport mechanism: in mice and humans, the FCh contained in HDL is rapidly cleared from the plasma (within minutes), independently of esterification and HDL holoparticle uptake by the liver. Moreover, the reversibility of FCh transfer between macrophages and HDL has implicated the reverse process - that is, the transfer of FCh from HDL to macrophages - in the aetiology of increased ASCVD under conditions of very high plasma HDL-FCh concentrations. In this Review, Gotto and colleagues summarize the evolution of our understanding of HDL structure and function, current models of atheroprotection by HDL involving reverse cholesterol transport, and their identification of a correlation between the bioavailability of free cholesterol contained in HDL and atherogenesis.

Automated summary

Plasma HDL-cholesterol levels are negatively correlated with the risk of ASCVD, but genetic approaches to increase HDL levels do not reduce this risk. The mechanism of reverse cholesterol transport involving FCh transfer between HDL and macrophages is still under debate in relation to ASCVD.