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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists

Published on: November 15, 2013

The nuclear bile acid receptor FXR is activated by PGC-1alpha in a ligand-dependent manner

Eiko Kanaya1, Takuma Shiraki, Hisato Jingami

  • 1Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3 Furuedai, Suita-City, Osaka 565-0874, Japan.

The Biochemical Journal
|June 19, 2004
PubMed

Insights

Peroxisome-proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) enhances the farnesoid X receptor

Area of Science:

  • Molecular Biology
  • Endocrinology
  • Metabolism

Background:

  • The farnesoid X receptor (FXR) is a nuclear receptor crucial for regulating bile acid biosynthesis in the liver.
  • Peroxisome-proliferator-activated receptor gamma co-activator-1alpha (PGC-1alpha) plays a key role in energy homeostasis across multiple tissues, including the liver.
  • Understanding co-activators of FXR is essential for elucidating bile acid metabolism regulation.

Purpose of the Study:

  • To identify co-activators that enhance the transcriptional activity of the farnesoid X receptor (FXR).
  • To investigate the role of PGC-1alpha as a potential FXR co-activator.
  • To explore the interaction between FXR, PGC-1alpha, and the small heterodimer partner (SHP) gene transcription.

Main Methods:

  • Cell-based reporter assays utilizing a GAL4-FXR chimera to assess transcriptional activation.
  • Co-immunoprecipitation and glutathione S-transferase (GST) pull-down assays to examine in vivo and in vitro protein-protein interactions.
  • Analysis of SHP gene transcription in the presence and absence of PGC-1alpha and chenodeoxycholic acid (CDCA).

Main Results:

  • PGC-1alpha significantly enhanced the ligand-dependent transcriptional activity of the GAL4-FXR chimera.
  • PGC-1alpha potentiated the transcriptional activation of the SHP gene by the FXR-retinoid X receptor alpha (RXRalpha) heterodimer in a CDCA-dependent manner.
  • Direct binding between the ligand-binding domain of FXR and PGC-1alpha was observed, influenced by ligand presence.

Conclusions:

  • PGC-1alpha acts as a co-activator for FXR, mediating ligand-dependent transcriptional activation.
  • PGC-1alpha enhances the transcription of the SHP gene, a known repressor of its own transcription.
  • The findings elucidate a novel mechanism by which PGC-1alpha modulates FXR activity and bile acid homeostasis.

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