The nuclear bile acid receptor FXR (farnesoid X receptor) is one of the key factors that suppress bile acid biosynthesis in the liver. PGC-1α [PPARγ (peroxisome-proliferator-activated receptor γ) co-activator-1α] is known to control energy homoeostasis in adipose tissue, skeletal muscle and liver. We performed cell-based reporter assays using the expression system of a GAL4–FXR chimaera, the ligand-binding domain of FXR fused to the DNA-binding domain of yeast GAL4, to find the co-activators for FXR. We found that the transcriptional activation of a reporter plasmid by a GAL4–FXR chimaera was strongly enhanced by PGC-1α, in a ligand-dependent manner. Transcriptional activation of the SHP (small heterodimer partner) gene by the FXR–RXRα (retinoid X receptor α) heterodimer was also enhanced by PGC-1α in the presence of CDCA (chenodeoxycholic acid). Co-immunoprecipitation and pull-down studies using glutathione S-transferase–PGC-1α fusion proteins revealed that the ligand-binding domain of FXR binds PGC-1α in a ligand-influenced manner both in vivo and in vitro. Furthermore, our studies revealed that SHP represses its own transcription, and the addition of excess amounts of PGC-1α can overcome the inhibitory effect of SHP. These observations indicate that PGC-1α mediates the ligand-dependent activation of FXR and transcription of SHP gene.
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Research Article|
September 07 2004
The nuclear bile acid receptor FXR is activated by PGC-1α in a ligand-dependent manner
Eiko KANAYA;
Eiko KANAYA
1Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3 Furuedai, Suita-City, Osaka 565-0874, Japan
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Takuma SHIRAKI;
Takuma SHIRAKI
1Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3 Furuedai, Suita-City, Osaka 565-0874, Japan
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Hisato JINGAMI
Hisato JINGAMI
1
1Department of Molecular Biology, Biomolecular Engineering Research Institute (BERI), 6-2-3 Furuedai, Suita-City, Osaka 565-0874, Japan
1To whom correspondence should be addressed (email [email protected]).
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Publisher: Portland Press Ltd
Received:
March 16 2004
Revision Received:
June 03 2004
Accepted:
June 17 2004
Accepted Manuscript online:
June 17 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 382 (3): 913–921.
Article history
Received:
March 16 2004
Revision Received:
June 03 2004
Accepted:
June 17 2004
Accepted Manuscript online:
June 17 2004
Citation
Eiko KANAYA, Takuma SHIRAKI, Hisato JINGAMI; The nuclear bile acid receptor FXR is activated by PGC-1α in a ligand-dependent manner. Biochem J 15 September 2004; 382 (3): 913–921. doi: https://doi.org/10.1042/BJ20040432
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