Title | Retinoic acid receptor-mediated induction of ABCA1 in macrophages. |
Publication Type | Journal Article |
Year of Publication | 2003 |
Authors | Costet P, Lalanne F, Gerbod-Giannone MC, Molina JR, Fu X, Lund EG, Gudas LJ, Tall AR |
Journal | Mol Cell Biol |
Volume | 23 |
Issue | 21 |
Pagination | 7756-66 |
Date Published | 2003 Nov |
ISSN | 0270-7306 |
Keywords | Animals, 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 |
Abstract | 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. |
DOI | 10.1128/mcb.23.21.7756-7766.2003 |
Alternate Journal | Mol. Cell. Biol. |
PubMed ID | 14560020 |
PubMed Central ID | PMC207565 |