Send to

Choose Destination
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

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.
Korea Research Institute of Bioscience and Biotechnology, Daejeon, 34141, Republic of Korea.
New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
Severance Biomedical Science Institute and Department of Internal Medicine, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu, 41404, Republic of Korea.
Boryung Central Research Institute, Ansan, 15425, Republic of Korea.
Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 34141, Republic of Korea.
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.



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.


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.


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

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center