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PLoS One. 2016 Jul 25;11(7):e0159425. doi: 10.1371/journal.pone.0159425. eCollection 2016.

The Orphan Nuclear Receptor ERRγ Regulates Hepatic CB1 Receptor-Mediated Fibroblast Growth Factor 21 Gene Expression.

Author information

1
National Creative Research Initiatives Center for Nuclear Receptor Signals and Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju, 61186, Republic of Korea.
2
Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
3
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
4
Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
5
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
6
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea.
7
Boryung Central Research Institute, Ansan, 15425, Republic of Korea.
8
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
9
Richard Roudebush Veterans Affairs Medical Center and the Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, United States of America.

Abstract

BACKGROUND:

Fibroblast growth factor 21 (FGF21), a stress inducible hepatokine, is synthesized in the liver and plays important roles in glucose and lipid metabolism. However, the mechanism of hepatic cannabinoid type 1 (CB1) receptor-mediated induction of FGF21 gene expression is largely unknown.

RESULTS:

Activation of the hepatic CB1 receptor by arachidonyl-2'-chloroethylamide (ACEA), a CB1 receptor selective agonist, significantly increased FGF21 gene expression. Overexpression of estrogen-related receptor (ERR) γ increased FGF21 gene expression and secretion both in hepatocytes and mice, whereas knockdown of ERRγ decreased ACEA-mediated FGF21 gene expression and secretion. Moreover, ERRγ, but not ERRα and ERRβ, induced FGF21 gene promoter activity. In addition, deletion and mutation analysis of the FGF21 promoter identified a putative ERRγ-binding motif (AGGTGC, a near-consensus response element). A chromatin immunoprecipitation assay revealed direct binding of ERRγ to the FGF21 gene promoter. Finally, GSK5182, an ERRγ inverse agonist, significantly inhibited hepatic CB1 receptor-mediated FGF21 gene expression and secretion.

CONCLUSION:

Based on our data, we conclude that ERRγ plays a key role in hepatic CB1 receptor-mediated induction of FGF21 gene expression and secretion.

PMID:
27455076
PMCID:
PMC4959684
DOI:
10.1371/journal.pone.0159425
[Indexed for MEDLINE]
Free PMC Article

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