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Ligand-dependent coactivation of the human bile acid receptor fxr by the peroxisome proliferator-activated receptor gamma coactivator-1 alpha

Academic Article
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Overview

authors

  • Savkur, R. S.
  • Thomas, J. S.
  • Bramlett, K. S.
  • Gao, Y. L.
  • Michael, L. F.
  • Burris, Thomas

publication date

  • 2005

journal

  • Journal of Pharmacology and Experimental Therapeutics  Journal

abstract

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

subject areas

  • Bile Acids and Salts
  • Cells, Cultured
  • Cholesterol
  • DNA-Binding Proteins
  • Heat-Shock Proteins
  • Humans
  • Ligands
  • Protein Structure, Tertiary
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Transcription, Genetic
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Identity

International Standard Serial Number (ISSN)

  • 0022-3565

Digital Object Identifier (DOI)

  • 10.1124/jpet.104.072124

PubMed ID

  • 15329387
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Additional Document Info

start page

  • 170

end page

  • 178

volume

  • 312

issue

  • 1

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