Retinoic acid receptor-mediated induction of ABCA1 in macrophages.

TitleRetinoic acid receptor-mediated induction of ABCA1 in macrophages.
Publication TypeJournal Article
Year of Publication2003
AuthorsCostet P, Lalanne F, Gerbod-Giannone MC, Molina JR, Fu X, Lund EG, Gudas LJ, Tall AR
JournalMol Cell Biol
Date Published2003 Nov
KeywordsAnimals, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Biological Transport, CCAAT-Enhancer-Binding Proteins, Cells, Cultured, Cholesterol, DNA-Binding Proteins, Gene Expression Regulation, Humans, Liver, Liver X Receptors, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Orphan Nuclear Receptors, Promoter Regions, Genetic, Receptors, Cytoplasmic and Nuclear, Receptors, Retinoic Acid, Sterol Regulatory Element Binding Protein 1, Transcription Factors, Tretinoin

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, RARgamma/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 RARgamma/RXR to the ABCA1 promoter DR4 element in the presence of ATRA, with weaker binding of RARalpha/RXR, and no binding of RARbeta/RXR. However, in macrophages from RARgamma(-/-) mice, TTNPB still induced ABCA1, in association with marked upregulation of RARalpha, suggesting that high levels of RARalpha can compensate for the absence of RARgamma. 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 LXRalpha). The more specific RAR activator TTNPB did not induce SREBP-1c in mouse primary macrophages or liver. These studies indicate a direct role of RARgamma/RXR in induction of macrophage ABCA1.

Alternate JournalMol. Cell. Biol.
PubMed ID14560020
PubMed Central IDPMC207565