Atherosclerosis, driven by inflamed
lipid-laden lesions, can occlude the coronary arteries and lead to
myocardial infarction. This
chronic disease is a major and expensive health burden. However, the body is able to mobilize and excrete
cholesterol and other
lipids, thus preventing
atherosclerosis by a process termed reverse
cholesterol transport (RCT). Insight into the mechanism of RCT has been gained by the study of two rare syndromes caused by the mutation of
ABC transporter loci. In
Tangier disease, loss of ABCA1 prevents cells from exporting
cholesterol and
phospholipid, thus resulting in the build-up of
cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop
atherosclerosis. Likewise,
sitosterolemia is another inherited syndrome associated with premature
atherosclerosis. Here mutations in either the ABCG5 or G8 loci, prevents hepatocytes and enterocytes from excreting
cholesterol and
plant sterols, including
sitosterol, into the bile and intestinal lumen. Thus, ABCG5 and G8, which from a heterodimer, constitute a transporter that excretes
cholesterol and dietary
sterols back into the gut, while ABCA1 functions to export excess cell
cholesterol and
phospholipid during the biogenesis of HDL. Interestingly, a third
protein, ABCG1, that has been shown to have anti-atherosclerotic activity in mice, may also act to transfer
cholesterol to mature HDL particles. Here we review the relationship between the
lipid transport activities of these
proteins and their anti-atherosclerotic effect, particularly how they may reduce inflammatory signaling pathways. Of particular interest are recent reports that indicate both ABCA1 and ABCG1 modulate cell surface
cholesterol levels and inhibit its partitioning into
lipid rafts. Given
lipid rafts may provide platforms for innate immune receptors to respond to inflammatory signals, it follows that loss of ABCA1 and ABCG1 by increasing raft content will increase signaling through these receptors, as has been experimentally demonstrated. Moreover, additional reports indicate ABCA1, and possibly SR-BI, another
HDL receptor, may directly act as anti-inflammatory receptors independent of their
lipid transport activities. Finally, we give an update on the progress and pitfalls of therapeutic approaches that seek to stimulate the flux of
lipids through the RCT pathway.