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Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.
Biochim Biophys Acta 2012; 1821(4):561-72BB

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.

Authors+Show Affiliations

Division of Anti-aging, Department of Internal Medicine, National Defense Medical College, Japan. ayoaori@ndmc.ac.jpNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22353356

Citation

Ayaori, Makoto, et al. "Retinoic Acid Receptor Agonists Regulate Expression of ATP-binding Cassette Transporter G1 in Macrophages." Biochimica Et Biophysica Acta, vol. 1821, no. 4, 2012, pp. 561-72.
Ayaori M, Yakushiji E, Ogura M, et al. Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages. Biochim Biophys Acta. 2012;1821(4):561-72.
Ayaori, M., Yakushiji, E., Ogura, M., Nakaya, K., Hisada, T., Uto-Kondo, H., ... Ikewaki, K. (2012). Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages. Biochimica Et Biophysica Acta, 1821(4), pp. 561-72. doi:10.1016/j.bbalip.2012.02.004.
Ayaori M, et al. Retinoic Acid Receptor Agonists Regulate Expression of ATP-binding Cassette Transporter G1 in Macrophages. Biochim Biophys Acta. 2012;1821(4):561-72. PubMed PMID: 22353356.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages. AU - Ayaori,Makoto, AU - Yakushiji,Emi, AU - Ogura,Masatsune, AU - Nakaya,Kazuhiro, AU - Hisada,Tetsuya, AU - Uto-Kondo,Harumi, AU - Takiguchi,Shunichi, AU - Terao,Yoshio, AU - Sasaki,Makoto, AU - Komatsu,Tomohiro, AU - Iizuka,Maki, AU - Yogo,Makiko, AU - Uehara,Yoshinari, AU - Kagechika,Hiroyuki, AU - Nakanishi,Tsuyoshi, AU - Ikewaki,Katsunori, Y1 - 2012/02/14/ PY - 2011/11/29/received PY - 2012/01/23/revised PY - 2012/02/06/accepted PY - 2012/2/23/entrez PY - 2012/2/23/pubmed PY - 2013/2/5/medline SP - 561 EP - 72 JF - Biochimica et biophysica acta JO - Biochim. Biophys. Acta VL - 1821 IS - 4 N2 - 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. SN - 0006-3002 UR - https://www.unboundmedicine.com/medline/citation/22353356/Retinoic_acid_receptor_agonists_regulate_expression_of_ATP_binding_cassette_transporter_G1_in_macrophages_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1388-1981(12)00031-5 DB - PRIME DP - Unbound Medicine ER -