Retinoic acid receptor-mediated induction of ABCA1 in macrophages.
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.
Costet
Philippe
P
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
Lalanne
Florent
F
Gerbod-Giannone
Marie C
MC
Molina
Jennifer R
JR
Fu
Xuan
X
Lund
Erik G
EG
Gudas
Lorraine J
LJ
Tall
Alan R
AR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000502:physiology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014212:Tretinoin / Q000378:metabolism
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; C497387:SREBF1 protein, human; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014212:Tretinoin; D002784:Cholesterol