Is it time to modify the reverse cholesterol transport model?

ABCA1 was recently identified as the mutant molecule in Tangier disease, a condition associated with very low HDL, cholesteryl ester accumulation in tissue macrophages, and an apparent increased risk of atherosclerotic cardiovascular disease. ABCA1 is an ATP-binding cassette transporter that facilitates the addition of phospholipids and cholesterol to free apoA-I, initiating the formation of HDL (1). ABCA1 is upregulated in cholesterolloaded cells, as a result of activation of LXR/RXR at the proximal promoter of the ABCA1 gene (2, 3). It has been proposed that increased expression of ABCA1 in macrophages or other tissues could activate the excretion of cholesterol via HDL and retard the development of atherosclerosis (3, 4). While we await the results of atherosclerosis studies, two reports in the JCI on ABCA1 knockout (KO) mice are notable, since they address different aspects of this hypothesis and reach some unexpected conclusions that call into question the accepted view of reverse cholesterol transport.