title: Mechanistic insights into isoform-dependent and species-specific regulation of bile salt export pump by farnesoid X receptor.
abstract: Expression of bile salt export pump (BSEP) is regulated by the bile acid/farnesoid X receptor (FXR) signaling pathway. Two FXR isoforms, FXRα1 and FXRα2, are predominantly expressed in human liver. We previously showed that human BSEP was isoform-dependently regulated by FXR and diminished with altered expression of FXRα1 and FXRα2 in patients with hepatocellular carcinoma. In this study, we demonstrate that FXRα1 and FXRα2 regulate human BSEP through two distinct FXR responsive elements (FXRE): IR1a and IR1b. As the predominant regulator, FXRα2 potently transactivated human BSEP through IR1a, while FXRα1 weakly transactivated human BSEP through a newly identified IR1b. Relative expression of FXRα1 and FXRα2 affected human BSEP expression in vitro and in vivo. Electrophoretic mobility shift and chromatin immunoprecipitation assays confirmed the binding and recruitment of FXRα1 and FXRα2 to IR1b and IR1a. Sequence analysis concluded that IR1b was completely conserved among species, whereas IR1a exhibited apparent differences across species. Sequence variations in IR1a were responsible for the observed species difference in BSEP transactivation by FXRα1 and FXRα2. In conclusion, FXR regulates BSEP in an isoform-dependent and species-specific manner through two distinct FXREs, and alteration of relative FXR isoform expression may be a potential mechanism for FXR to precisely regulate human BSEP in response to various physiological and pathological conditions.
authors.affiliation: Department of Biomedical and Pharmaceutical Sciences, Center for Pharmacogenomics and Molecular Therapy, University of Rhode Island, Kingston, RI 02881.
authors.forename: Xiulong
authors.initials: X
authors.lastname: Song
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Leila
authors.initials: L
authors.lastname: Valanejad
authors.forename: Rajani
authors.initials: R
authors.lastname: Kaimal
authors.forename: Bingfang
authors.initials: B
authors.lastname: Yan
authors.forename: Matthew
authors.initials: M
authors.lastname: Stoner
authors.forename: Ruitang
authors.initials: R
authors.lastname: Deng
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D055029:Inverted Repeat Sequences; D008024:Ligands; D008099:Liver / Q000378:metabolism; D051379:Mice; D009154:Mutation; D020033:Protein Isoforms / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D013045:Species Specificity; D015533:Transcriptional Activation; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D008024:Ligands; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C093491:ABCB11 protein, human; C490549:Abcb11 protein, mouse; C490548:Abcb11 protein, rat
keywords: bile acid transporter; canalicular secretion; gene transcription