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Received for publication June 2, 2004.
Revised August 5, 2004.
Accepted for publication August 24, 2004.
Coactivator-1
(PGC-1)
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- (LXR) and inducing the expression of cholesterol 7--hydroxylase (CYP7A1). Here we demonstrate that PGC-1 also functions as an effective coactivator of 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, GST 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 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 LBD of FXR in PGC-1 recognition. Taken 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.
Key words:
bile acid, fxr, nuclear receptor, oxysterol, steroid receptor, transcription
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