Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor gamma Coactivator-lalpha

摘要

Peroxisome proliferator-activated receptor y coactivatoMa(PGC-1 a) has been shown to play an important role in energy metabolism by coordinating transcriptional programs involved in mitochondrial biogenesis,adaptive thermogenesis,gluconeogen-esis,and fatty acid oxidation.PGC-1 a also plays a crucial role in cholesterol metabolism by serving as a coactivator of the liver X receptor-a and inducing the expression of cholesterol 7-alpha-hgamma-droxylase.Here,we demonstrate that PGC-1 a also functions as an effective coactivator of farnesoid X receptor(FXR),the bile acid receptor.Transient cotransfection assays demonstrate that PGC-1 a enhances ligand-mediated FXR transcription when either full-length FXR or Gal4 DNA binding domain-FXR-ligand binding domain chimeras were analyzed.Mammalian two-hybrid analyses,glutathione S-transferase affinity chromatogralpha-phy and biochemical coactivator recruitment assays demonstrate ligand-dependent interaction between the two proteins both in vivo and in vitro.PGC-1 alpha-mediated coactivation of FXR was highly ligand-dependent and absolutely required an intact activation function-2(AF-2) domain of FXR and the LXXLL motif in PGC-1 a.The integrity of the charge clamp was required,further illustrating the role of the ligand binding domain of FXR in PGC-1 a recognition.Together,these results indicate that PGC-1 a functions as a potent coactivator for FXR and further implicates its role in the regulation of genes that are involved in bile acid and lipid metabolism.