title: The nuclear bile acid receptor FXR is activated by PGC-1alpha in a ligand-dependent manner.
abstract: The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key factors that suppress bile acid biosynthesis in the liver. PGC-1alpha [PPARgamma (peroxisome-proliferator-activated receptor gamma) co-activator-1alpha] is known to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We performed cell-based reporter assays using the expression system of a GAL4-FXR chimaera, the ligand-binding domain of FXR fused to the DNA-binding domain of yeast GAL4, to find the co-activators for FXR. We found that the transcriptional activation of a reporter plasmid by a GAL4-FXR chimaera was strongly enhanced by PGC-1alpha, in a ligand-dependent manner. Transcriptional activation of the SHP (small heterodimer partner) gene by the FXR-RXRalpha (retinoid X receptor alpha) heterodimer was also enhanced by PGC-1alpha in the presence of CDCA (chenodeoxycholic acid). Co-immunoprecipitation and pull-down studies using glutathione S-transferase-PGC-1alpha fusion proteins revealed that the ligand-binding domain of FXR binds PGC-1alpha in a ligand-influenced manner both in vivo and in vitro. Furthermore, our studies revealed that SHP represses its own transcription, and the addition of excess amounts of PGC-1alpha can overcome the inhibitory effect of SHP. These observations indicate that PGC-1alpha mediates the ligand-dependent activation of FXR and transcription of SHP gene.
authors.affiliation: Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3 Furuedai, Suita-City, Osaka 565-0874, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Kanaya
authors.forename: Takuma
authors.initials: T
authors.lastname: Shiraki
authors.forename: Hisato
authors.initials: H
authors.lastname: Jingami
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001665:Binding Sites; D019556:COS Cells; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism*; D006360:Heat-Shock Proteins / Q000502:physiology*; D008024:Ligands; D046912:Multiprotein Complexes / Q000737:chemistry; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017434:Protein Structure, Tertiary; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D047490:Retinoid X Receptor alpha / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D008024:Ligands; D046912:Multiprotein Complexes; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D018160:Receptors, Cytoplasmic and Nuclear; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D047490:Retinoid X Receptor alpha; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C486497:PPARGC1A protein, human; C099713:nuclear receptor subfamily 0, group B, member 2