title: Identification of gene-selective modulators of the bile acid receptor FXR.
abstract: BAR is a nuclear bile acid receptor (BAR) (FXR) receptor that regulates gene networks involved in cholesterol and bile acid homeostasis. We have identified two classes of synthetic compounds that differentially modulate BAR activity. The first class activates BAR target genes in the predicted fashion and is 25-fold more potent than endogenous bile acids. The second class, represented by AGN34, antagonizes BAR in transient reporter assays. Surprisingly, this compound acts in a gene-selective manner in vivo: it is an agonist on CYP7A1, an antagonist on IBABP, and is neutral on SHP. These findings indicate that synthetic BAR modulators can be developed to regulate transcription in a gene-specific fashion. Given the ability of BAR to regulate several lipid homeostatic pathways, the identification of gene-selective BAR modulators have important implications for the development of improved cholesterol lowering agents.
authors.affiliation: Division of Molecular Medicine, The Beckman Research Institute, the City of Hope National Medical Center, The Gonda Diabetes & Genetic Research Center, Duarte, California 91010, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dussault
authors.forename: Rick
authors.initials: R
authors.lastname: Beard
authors.forename: Min
authors.initials: M
authors.lastname: Lin
authors.forename: Kevin
authors.initials: K
authors.lastname: Hollister
authors.forename: Jasmine
authors.initials: J
authors.lastname: Chen
authors.forename: Jia-Hao
authors.initials: JH
authors.lastname: Xiao
authors.forename: Rosh
authors.initials: R
authors.lastname: Chandraratna
authors.forename: Barry M
authors.initials: BM
authors.lastname: Forman
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001667:Binding, Competitive; D015152:Blotting, Northern; D002210:Caprylates / Q000494:pharmacology; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008956:Models, Chemical; D010647:Phenyl Ethers / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002210:Caprylates; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D008024:Ligands; D010647:Phenyl Ethers; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C472778:AGN 34 compound