title: Constitutive androstane/active receptor is a target of retinoic acid receptor in humans.
abstract: Nuclear receptor constitutive androstane/active receptor (CAR) is well known as a transcription factor regulating many genes that encode drug-metabolizing enzymes and factors modulating hepatic gluconeogenesis. However, there have been few studies on regulation of the CAR gene itself. In this study, we examined the involvement of retinoic acid receptor alpha (RAR alpha) in transcriptional regulation of the CAR gene in the liver. The expression levels of CAR mRNA in human primary hepatocytes and HepG2 cells were increased by all-trans retinoic acid. Activities of the human CAR promoter containing a region (termed cRARE) located at +1453/+1469 within intron 1 were increased by co-expression of RAR alpha in HepG2 cells. In addition, introduction of mutation into cRARE abolished transcriptional activation of the promoter by RAR alpha. The results of gel mobility shift assay and chromatin immunoprecipitation assay showed that RAR alpha was bound to cRARE. These results suggest that RAR alpha transactivated the human CAR gene by binding to cRARE located at +1453/+1469 within intron 1 of the gene. In contrast, the rat CAR gene was not activated by exposure to all-trans retinoic acid, probably due to the lack of a region corresponding to cRARE in the human CAR gene. Although the physiological significance of RAR alpha-dependent up-regulation of CAR in the human liver remains to be clarified, retinoid metabolism may be regulated by the up-regulation of CAR.
authors.affiliation: Laboratory of Pharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8675, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Saito
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Mizuno
authors.forename: Tomomi
authors.initials: T
authors.lastname: Furihata
authors.forename: Kan
authors.initials: K
authors.lastname: Chiba
mesh_terms: D000731:Androstanes / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D000090702:Constitutive Androstane Receptor; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007438:Introns; D008113:Liver Neoplasms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000378:metabolism
chemical_list: D000731:Androstanes; D002352:Carrier Proteins; D000090702:Constitutive Androstane Receptor; C000607071:RARA protein, human; D012333:RNA, Messenger; C000607073:Rara protein, rat; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D014212:Tretinoin; C033936:androstane