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CELLULAR AND MOLECULAR

Ligand-Dependent Coactivation of the Human Bile Acid Receptor FXR by the Peroxisome Proliferator-Activated Receptor Coactivator-1

Eli Lilly & Company, Lilly Research Laboratories, Indianapolis, Indiana (R.S.S., J.S.T., K.S.B., Y.G., L.F.M., T.P.B.); and Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana (K.S.B., T.P.B.)

Peroxisome proliferator-activated receptor coactivator-1 (PGC-1) 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-1 also plays a crucial role in cholesterol metabolism by serving as a coactivator of the liver X receptor- and inducing the expression of cholesterol 7--hydroxylase. Here, we demonstrate that PGC-1 also functions as an effective coactivator of farnesoid X receptor (FXR), the bile acid receptor. Transient cotransfection assays demonstrate that PGC-1 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-1-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. The integrity of the charge clamp was required, further illustrating the role of the ligand binding domain of FXR in PGC-1 recognition. Together, these results indicate that PGC-1 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.

Address correspondence to: Dr. Thomas P. Burris, Eli Lilly & Company, DC0434, Lilly Corporate Center, Indianapolis, IN 46285. E-mail: burris{at}lilly.com

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