Regulation of reverse cholesterol transport - a comprehensive appraisal of available animal studies

Large population studies conclusively demonstrated that plasma levels of high density lipoprotein cholesterol (HDL-C) as well as its major apolipoprotein constituent apolipoprotein A-I (apoA-I) are inversely associated with the risk of atherosclerotic cardiovascular disease [1-4]. However, within these study populations there is still a substantial number of patients that experience complications of cardiovascular disease despite considerably high HDL-C plasma levels [1,2,4], and vice versa there are individuals with low plasma HDL-C levels that do not develop clinically significant atherosclerosis [1,2,4]. Such observations lead to the investigation how HDL particles confer protection against atherosclerosis. One of the earliest recognized functions of HDL is that it promotes cholesterol efflux from macrophage foam cells, which constitute the hallmark cell type of atherosclerotic lesions [5,6]. Upon entrance into the vessel wall monocytes become macrophages and take up vast amounts of modified pro-atherogenic apoB-containing lipoproteins that are accumulating within the vascular wall as an early event in the process of atherogenesis [7,8]. Uptake of cholesterol immobilizes macrophages within the vessel wall resulting in a sustained inflammatory response [8,9]. Importantly, cholesterol efflux from foam cells can revert this phenotype leading to macrophage egress from lesions and a subsequent reduction in lesion burden [10]. HDL-mediated cholesterol efflux therefore constitutes a key step not only for preventing lesion progression but also for clinical efforts to induce regression of preexisting atherosclerotic plaques. Subsequently, the cholesterol effluxed from foam cells towards HDL should ideally be irreversibly eliminated from the body to prevent re-uptake into the vessel wall. This goal is achieved by a complex multistep process that has been coined reverse cholesterol transport (RCT) [5,10,11].Reverse cholesterol transport is a term that comprises all the diff