title: Retinoic acid receptor agonists regulate expression of ATP-binding cassette transporter G1 in macrophages.
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.affiliation: Division of Anti-aging, Department of Internal Medicine, National Defense Medical College, Japan. ayoaori@ndmc.ac.jp
authors.forename: Makoto
authors.initials: M
authors.lastname: Ayaori
authors.forename: Emi
authors.initials: E
authors.lastname: Yakushiji
authors.forename: Masatsune
authors.initials: M
authors.lastname: Ogura
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Nakaya
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Hisada
authors.forename: Harumi
authors.initials: H
authors.lastname: Uto-Kondo
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takiguchi
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Terao
authors.forename: Makoto
authors.initials: M
authors.lastname: Sasaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Komatsu
authors.forename: Maki
authors.initials: M
authors.lastname: Iizuka
authors.forename: Makiko
authors.initials: M
authors.lastname: Yogo
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Uehara
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Nakanishi
authors.forename: Katsunori
authors.initials: K
authors.lastname: Ikewaki
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D001692:Biological Transport / Q000187:drug effects; D015153:Blotting, Western; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D000071518:Liver X Receptors; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008957:Models, Genetic; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000235:genetics; D047488:Retinoid X Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D001565:Benzoates; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors; D012176:Retinoids; D013764:Tetrahydronaphthalenes; C068073:Am 580; D014212:Tretinoin; C038864:4-(2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid; D002784:Cholesterol