RRC ID 43681
著者 Ayaori M, Yakushiji E, Ogura M, Nakaya K, Hisada T, Uto-Kondo H, Takiguchi S, Terao Y, Sasaki M, Komatsu T, Iizuka M, Yogo M, Uehara Y, Kagechika H, Nakanishi T, Ikewaki K.
タイトル Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.
ジャーナル Biochim Biophys Acta
Abstract ABC transporter G1 (ABCG1) plays a pivotal role in HDL-mediated cholesterol efflux and atherogenesis. We investigated whether, and how, retinoic acid receptors (RARs) regulate ABCG1 expression in macrophages. All-trans retinoic acid (ATRA), an RAR ligand, increased ABCG1 protein levels and apoA-I/HDL-mediated cholesterol efflux from the macrophages. Both ATRA and other RAR agonists, TTNPB and Am580, increased major transcripts driven by promoter B upstream of exon 5, though minor transcripts driven by promoter A upstream of exon 1 were only increased by ATRA. The stimulatory effects of ATRA on ABCG1 expression were completely abolished in the presence of RAR/RXR antagonists but were only partially canceled in the presence of an LXR antagonist. Adenovirus with overexpressed oxysterol sulfotransferase abolished the LXR pathway, as previously reported, and ATRA-responsiveness in ABCA1/ABCG1 expressions were respectively attenuated by 38 and 22% compared to the control virus. Promoter assays revealed that ABCG1 levels were regulated more by promoter B than promoter A, and ATRA activated promoter B in a liver X receptor-responsive element (LXRE)-dependent manner. Further, LXRE-B in intron 7, but not LXRE-A in intron 5, enhanced ATRA responsiveness under overexpression of all RAR isoforms-RARα/β/γ. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RARα, but not on RARβ/γ. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RARα to LXRE-B. In conclusion, RAR ligands increase ABCA1/G1 expression and apoA-I/HDL-mediated cholesterol efflux from macrophages, and modulate ABCG1 promoter activity via LXRE-dependent mechanisms.
巻・号 1821(4)
ページ 561-72
公開日 2012-4-1
DOI 10.1016/j.bbalip.2012.02.004
PII S1388-1981(12)00031-5
PMID 22353356
MeSH ATP Binding Cassette Transporter 1 ATP Binding Cassette Transporter, Subfamily G, Member 1 ATP-Binding Cassette Transporters / genetics ATP-Binding Cassette Transporters / metabolism* Animals Benzoates / pharmacology Biological Transport / drug effects Blotting, Western COS Cells Cell Line Chlorocebus aethiops Cholesterol / metabolism Gene Expression Regulation / drug effects HEK293 Cells Humans Liver X Receptors Macrophages / cytology Macrophages / drug effects* Macrophages / metabolism Models, Genetic Orphan Nuclear Receptors / agonists Orphan Nuclear Receptors / genetics Orphan Nuclear Receptors / metabolism Promoter Regions, Genetic / genetics Protein Binding / drug effects Receptors, Retinoic Acid / agonists* Receptors, Retinoic Acid / genetics Receptors, Retinoic Acid / metabolism Response Elements / genetics Retinoid X Receptors / agonists Retinoid X Receptors / genetics Retinoid X Receptors / metabolism Retinoids / pharmacology Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Tetrahydronaphthalenes / pharmacology Tretinoin / pharmacology*
IF 3.411
引用数 15
WOS 分野 BIOPHYSICS BIOCHEMISTRY & MOLECULAR BIOLOGY CELL BIOLOGY
リソース情報
ヒト・動物細胞 RAW 264(RCB0535) 293(RCB1637) COS-7(RCB0539)