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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1930.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Stimulation of Cholesterol Efflux by LXR Agonists in Cholesterol-Loaded Human Macrophages Is ABCA1-Dependent but ABCG1-Independent

Sandra Larrede; Carmel M. Quinn; Wendy Jessup; Eric Frisdal; Maryline Olivier; Victar Hsieh; Mi-Jurng Kim; Miranda Van Eck; Philippe Couvert; Alain Carrie; Philippe Giral; M. John Chapman; Maryse Guerin; Wilfried Le Goff

From INSERM, UMR S939 (S.L., E.F., M.O., P.C., A.C., P.G., M.J.C., M.G., W.L.G.), Paris, France; Université Pierre et Marie Curie–Paris6 (S.L., E.F., M.O., P.C., A.C., P.G., M.J.C., M.G., W.L.G.), UMR S939 Paris, France; AP-HP, Groupe hospitalier Pitié-Salpétrière, Service de Biochimie Endocrinienne et Oncologique (P.C., A.C.) and Service d’Endocrinologie-Métabolisme (P.G.), Paris, France; the Centre for Vascular Research (C.M.Q., W.J., V.H., M.-J.K.), School of Medical Sciences, University of New South Wales, Sydney, Australia; and the Division of Biopharmaceutics (M.V.E.), Leiden/Amsterdam Center for Drug Research, Leiden University, The Netherlands.

Correspondence to Wilfried Le Goff, PhD, INSERM UMR S939, Hôpital de la Pitié, Pavillon Benjamin Delessert, 83, boulevard de l’Hôpital, 75651 Paris Cedex 13, France. E-mail wilfried.le_goff{at}upmc.fr

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 cells involves an ATP-dependent transport mechanism mediated by ABCA1 that it appears to be independent of ABCG1 expression.

Key Words: ABC transporters • LXR agonists • cholesterol efflux • macrophage • foam cells