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Molecular and Cellular Biology, November 2003, p. 7756-7766, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7756-7766.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Retinoic Acid Receptor-Mediated Induction of ABCA1 in Macrophages

Philippe Costet,1,{dagger} Florent Lalanne,1* Marie C. Gerbod-Giannone,1 Jennifer R. Molina,1 Xuan Fu,2 Erik G. Lund,2 Lorraine J. Gudas,3 and Alan R. Tall1

Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032,1 Department of Atherosclerosis and Endocrinology, Merck Research Laboratories, Rahway, New Jersey 07065,2 Department of Pharmacology, Weill Medical College of Cornell University, New York, New York 100213

Received 5 February 2003/ Accepted 25 July 2003

ABCA1, the mutant molecule in Tangier Disease, mediates efflux of cellular cholesterol to apoA-I and is induced by liver X receptor (LXR)/retinoid X receptor (RXR) transcription factors. Retinoic acid receptor (RAR) activators (all-trans-retinoic acid [ATRA] and TTNPB) were found to increase ATP-binding cassette transporter 1 (ABCA1) mRNA and protein in macrophages. In cellular cotransfection assays, RAR{gamma}/RXR activated the human ABCA1 promoter, via the same direct repeat 4 (DR4) promoter element as LXR/RXR. Chromatin immunoprecipitation analysis in macrophages confirmed the binding of RAR{gamma}/RXR to the ABCA1 promoter DR4 element in the presence of ATRA, with weaker binding of RAR{alpha}/RXR, and no binding of RARß/RXR. However, in macrophages from RAR{gamma}-/- mice, TTNPB still induced ABCA1, in association with marked upregulation of RAR{alpha}, suggesting that high levels of RAR{alpha} can compensate for the absence of RAR{gamma}. Dose-response experiments with ATRA in mouse primary macrophages showed that other LXR target genes were weakly induced (ABCG1 and SREBP-1c) or not induced (apoE and LXR{alpha}). The more specific RAR activator TTNPB did not induce SREBP-1c in mouse primary macrophages or liver. These studies indicate a direct role of RAR{gamma}/RXR in induction of macrophage ABCA1.

* Corresponding author. Mailing address: Division of Molecular Medicine, Department of Medicine, P&S 8-401, New York, NY 10032. Phone: (212) 305-5789. Fax: (212) 305-5052. E-mail: fl2002{at}columbia.edu.

{dagger} Present address: INSERM U539, CHU Hotel Dieu, 44000 Nantes, France.

Molecular and Cellular Biology, November 2003, p. 7756-7766, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7756-7766.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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