However, not all studies show a clear association between HDL-cholesterol and cardiovascular disease. 4,5 The observation that the capacity of serum to promote macrophage Molecular Medicine© 2015 American Heart Association, Inc. Objective: Our aims were to determine which HDL particle subfractions are most efficient in mediating cellular cholesterol efflux from foam cell macrophages and to identify the cellular cholesterol transporters involved in this process. Methods and Results:We used reconstituted HDL particles of defined size and composition, isolated subfractions of human plasma HDL, cell lines stably expressing ABCA1 or ABCG1, and both mouse and human macrophages in which ABCA1 or ABCG1 expression was deleted. We show that ABCA1 is the major mediator of macrophage cholesterol efflux to HDL, demonstrating most marked efficiency with small, dense HDL subfractions (HDL3b and HDL3c). ABCG1 has a lesser role in cholesterol efflux and a negligible role in efflux to HDL3b and HDL3c subfractions. Conclusions:

Objective-Maintenance of cholesterol homeostasis in human macrophages is essential to prevent foam cell formation. We evaluated the relative contribution of the ABCA1 and ABCG1 transporters to cholesterol efflux from human macrophages, and of the capacity of LXR agonists to reduce foam cell formation by stimulating export of cellular cholesterol. Methods and Results-ABCG1 mRNA levels were strongly increased in acLDL-loaded THP-1 macrophages and in HMDM on stimulation with LXR agonists. However, silencing of ABCG1 expression using ABCG1-specific siRNA indicated that ABCG1 was not essential for cholesterol efflux to HDL in cholesterol-loaded human macrophages stimulated with LXR agonists. Indeed, ABCA1 was solely responsible for the stimulation of cholesterol efflux to HDL on LXR activation, as this effect was abolished in HMDM from Tangier patients. Furthermore, depletion of cellular ATP indicated that the LXR-induced export of cholesterol was an ATP-dependent transport mechanism in human macrophages. Finally, use of an anti-Cla-1 blocking antibody identified the Cla-1 receptor as a key component in cholesterol efflux to HDL from cholesterol-loaded human macrophages. Conclusion-Our data indicate that stimulation of cholesterol efflux to HDL by LXR agonists in human foam cellsinvolves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression. Key Words: ABC transporters Ⅲ LXR agonists Ⅲ cholesterol efflux Ⅲ macrophage Ⅲ foam cells I n atherosclerotic lesions, the accumulation of cellular cholesterol within macrophage "foam cells" drives lipid deposition and is a major contributor to lesion growth. It is understood that macrophages become foam cells as the result of a loss of the normal balance between cholesterol uptake (from lipoproteins) and cholesterol export. For this reason, the mechanisms by which macrophages export cellular cholesterol have been intensively investigated in recent years.It is now generally accepted that HDL and its apolipoproteins are the major initial acceptors of excess cellular cholesterol. Members of the ABC transporter family have been identified as key, and potentially complementary, cellular participants in export of cholesterol to these acceptors. ABCA1 mediates cholesterol efflux most efficiently to lipidpoor apolipoprotein AI (apoAI), whereas ABCG1 promotes cholesterol export to lipidated particles such as HDL. In addition, the SR-BI receptor pathway can also promote cholesterol export to HDL particles.The contributions of ABCA1 and ABCG1 to the maintenance of macrophage cholesterol homeostasis have been most convincingly demonstrated through the effects of targeted deletion of these transporters in mice. 1 In particular, the profound effects of combined deletion of both ABCA1 and ABCG1 in mouse macrophages on their accumulation of cholesterol in vivo and on their ability to export cholesterol to either apoAI or to HDL in vitro, suggests that the combined activity of both of these transporters is essential for macrophage cholester...