ABSTRACT
Table 6.1 Summary of therapeutic strategies to promote macrophage cholesterol efflux and reverse cholesterol transport
Therapeutic strategy
Effect on HDL-C levels
Effect on macrophage RCT in vivo
Effect on atherosclerosis
Limitations
Strategy for increasing macrophage cholesterol effluxLXR agonists Variable Increase Decrease Induction of hepatic steatosis PPARα agonists Increase Increase Decrease Specificity and selectivity Strategy for improving quantity and functionality of HDL-based acceptorsSmall molecule upregulationof apoA-I Increase Unknown Unknown Limited human efficacy dataApoA-I/Reconstituted HDL infusions None/increase Unknown Decrease Limited human efficacy data, need for intravenous administrationApoA-I mimetic peptides None Increase Decrease Limited human efficacy data, need for intravenous administrationCETP inhibitors Increase Variable Unknown Failure of one molecule raised doubts about mechanism The removal of excess cholesterol from macrophage foam cells by HDL-based acceptors, including its principal apolipoprotein, apoA-1, is thought to be one of key mechanisms underlying the macrophage RCT [11]. ATP-binding cassette transporters ABCA1 and ABCG1 play a pivotal role in cholesterol efflux from macrophage foam cells. ABCA1 and ABCG1 also show additive activity in promoting macrophage RCT in vivo [12], and combined deficiency of these transporters in
bone marrow-derived hematopoietic cells leads to severe defects in cholesterol efflux to HDL, resulting in massive cholesteryl ester accumulation in macrophages and accelerated atherogenesis in susceptible mouse models [13, 14]. Collectively, scrutiny of the subtleties of the RCT pathway and HDL particle heterogeneity might offer a way forward in the development of HDL-centric therapeutics. This article aims to review methodologies of strategies for augmenting macrophage cholesterol efflux, which in turn promotes overall macrophage RCT, by regulating specific cellular transporters and enhancing acceptor functionality of circulating HDL (Table 6.1). 6.2 The Role of ABC Transporters, and the
by converting free cholesterol to cholesteryl ester or by effluxing cholesterol to extracellular acceptors. The rate of cellular cholesterol efflux is function of cholesterol status in the cell, the level of expression of cholesterol transporters, and the composition and concentration of extracellular cholesterol acceptors, generally HDL or its specific subfractions. The most abundant protein in HDL is apoA-I, which in a lipid-poor form is one type of acceptor; mature HDL particles also serve as acceptors of cellular cholesterol efflux (Fig. 6.1). A variety of specific pathways of cholesterol efflux have been defined, including: (1) efflux to lipid-poor apolipoproteins, particularly apoA-I, mediated by ABCA1; (2) efflux to mature HDL particles mediated by ABCG1; (3) efflux to mature HDL particles by other pathways, including scavenger receptor-BI (SR-BI); and finally (4) passive diffusion. While it was once assumed that passive diffusion was the primary process, recent research has demonstrated that macrophage cholesterol efflux occurs largely via ABCA1 and ABCG1.
