RT Journal Article SR Electronic T1 Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor γ Coactivator-1α JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 170 OP 178 DO 10.1124/jpet.104.072124 VO 312 IS 1 A1 Rajesh S. Savkur A1 Jeffrey S. Thomas A1 Kelli S. Bramlett A1 Yunling Gao A1 Laura F. Michael A1 Thomas P. Burris YR 2005 UL http://jpet.aspetjournals.org/content/312/1/170.abstract AB Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) has been shown to play an important role in energy metabolism by coordinating transcriptional programs involved in mitochondrial biogenesis, adaptive thermogenesis, gluconeogenesis, and fatty acid oxidation. PGC-1α also plays a crucial role in cholesterol metabolism by serving as a coactivator of the liver X receptor-α and inducing the expression of cholesterol 7-α-hydroxylase. Here, we demonstrate that PGC-1α also functions as an effective coactivator of farnesoid X receptor (FXR), the bile acid receptor. Transient cotransfection assays demonstrate that PGC-1α 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 chromatography and biochemical coactivator recruitment assays demonstrate ligand-dependent interaction between the two proteins both in vivo and in vitro. PGC-1α-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-1α. The integrity of the charge clamp was required, further illustrating the role of the ligand binding domain of FXR in PGC-1α recognition. Together, these results indicate that PGC-1α 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. The American Society for Pharmacology and Experimental Therapeutics