Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages

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• 作者：Makoto Ayaori^a ; ^{ayaori@ndmc.ac.jp} ; Emi Yakushiji^a ; Masatsune Ogura^a ; Kazuhiro Nakaya^a ; Tetsuya Hisada^b ; Harumi Uto-Kondo^a ; Shunichi Takiguchi^a ; Yoshio Terao^a ; Makoto Sasaki^a ; Tomohiro Komatsu^a ; Maki Iizuka^a ; Makiko Yogo^a ; Yoshinari Uehara^c ; Hiroyuki Kagechika^d ; Tsuyoshi Nakanishi^e ; Katsunori Ikewaki^a
• 关键词：ABCA1 ; ATP-binding cassette transporter A1 ; ABCG1 ; ATP-binding cassette transporter G1 ; AcLDL ; acetylated low-density lipoprotein ; apoA-I ; apolipoprotein A-I ; ATRA ; all-trans retinoic acid ; BSA ; bovine serum albumin ; DMEM ; Dulbecco's modified Eagle's medi
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular and Cell Biology of Lipids
• 出版年：2012
• 期刊代码：18_13881981
• 类别：bio
• 出版时间：April, 2012
• 卷：1821
• 期：4
• 页码：561-572
• 文件大小：1501 K

摘要

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鈥擱AR伪/尾/纬. In contrast, the activation of promoter B by TTNPB depended on LXRE-B and RAR伪, but not on RAR尾/纬. Finally, chromatin immunoprecipitation and gel-shift assays revealed a specific and direct repeat 4-dependent binding of RAR伪 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.