A New Frontier for Reverse Cholesterol Transport

Numerous epidemiological studies have demonstrated that high-density lipoprotein cholesterol (HDL-C) levels are inversely associated with cardiovascular risk. However, despite intense efforts to develop new pharmacological strategies to increase HDL-C levels, such as with niacin and cholesteryl ester transfer protein inhibitors, few robust associations with improved clinical outcomes have been observed. This failure of HDL-raising interventions has been accompanied by a shift toward gaining a more rigorous, basic understanding of HDL as a molecule with multiple functions that can be differentiated from simple measures of HDL-C mass. Reverse cholesterol transport (RCT) is a pivotal pathway involved in the return of excess cholesterol from peripheral tissues to the liver for excretion in the bile and eventually the feces. RCT and cholesterol efflux, the first step and a highly important component of the mechanism of RCT from macrophages in atherosclerotic plaques, are crucial to the antiatherogenicity of HDL. In human studies, it has been shown that the capacity of HDL to promote cholesterol efflux from macrophages ex vivo is inversely related to the risk of cardiovascular disease even after adjusting for HDL-C levels. Furthermore, although niacin treatment raises HDL levels in statin-treated patients, it does not augment cholesterol efflux, which could explain lack of efficacy of niacin. In view of this, an increasing number of studies have investigated the hypothesis that specific therapies, such as those using reconstituted HDL and various drugs, could increase cholesterol efflux and RCT and thereby improve cardiovascular outcomes.