Orphan nuclear receptor estrogen-related receptor γ(ERRγ) is key regulator of hepatic gluconeogenesis

Don Kyu Kim, Dongryeol Ryu, Minseob Koh, Min Woo Lee, Donghyun Lim, Min Jung Kim, Yong Hoon Kim, Won Jea Cho, Chul Ho Lee, Seung Bum Park, Seung-Hoi Koo, Hueng Sik Choi

Research output: Contribution to journalArticle

65 Citations (Scopus)

Abstract

Glucose homeostasis is tightly controlled by hormonal regulation of hepatic glucose production. Dysregulation of this system is often associated with insulin resistance and diabetes, resulting in hyperglycemia in mammals. Here, we show that the orphan nuclear receptor estrogen-related receptorγ (ERRγ) is a novel downstream mediator of glucagon action in hepatic gluconeogenesis and demonstrate a beneficial impact of the inverse agonist GSK5182. Hepatic ERRγ expression was increased by fasting-dependent activation of the cAMP-response element-binding protein-CRTC2 pathway. Overexpression of ERRγinduced Pck1 and G6PC gene expression and glucose production in primary hepatocytes, whereas abolition of ERRγ gene expression attenuated forskolin-mediated induction of gluconeogenic gene expression. Deletion and mutation analyses of the Pck1 promoter showed that ERRγ directly regulates the Pck1 gene transcription via ERR response elements of the Pck1 promoter as confirmed by ChIP assay and in vivo imaging analysis. Wealso demonstrate that GSK5182, an inverse agonist of ERRγ, specifically inhibits the transcriptional activity of ERRγ in a PGC-1α dependent manner. Finally, the ERRγ inverse agonist ameliorated hyperglycemia through inhibition of hepatic gluconeogenesis in db/db mice. Control of hepatic glucose production by an ERRγ-specific inverse agonist is a new potential therapeutic approach for the treatment of type 2 diabetes.

Original languageEnglish
Pages (from-to)21628-21639
Number of pages12
JournalJournal of Biological Chemistry
Volume287
Issue number26
DOIs
Publication statusPublished - 2012 Jun 22
Externally publishedYes

Fingerprint

Orphan Nuclear Receptors
Gluconeogenesis
Estrogen Receptors
Estrogens
Liver
Gene expression
Glucose
Gene Expression
Hyperglycemia
Medical problems
Cyclic AMP Response Element-Binding Protein
Sequence Deletion
Response Elements
Mammals
Colforsin
Glucagon
Transcription
Type 2 Diabetes Mellitus
Insulin Resistance
Hepatocytes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Orphan nuclear receptor estrogen-related receptor γ(ERRγ) is key regulator of hepatic gluconeogenesis. / Kim, Don Kyu; Ryu, Dongryeol; Koh, Minseob; Lee, Min Woo; Lim, Donghyun; Kim, Min Jung; Kim, Yong Hoon; Cho, Won Jea; Lee, Chul Ho; Park, Seung Bum; Koo, Seung-Hoi; Choi, Hueng Sik.

In: Journal of Biological Chemistry, Vol. 287, No. 26, 22.06.2012, p. 21628-21639.

Research output: Contribution to journalArticle

Kim, DK, Ryu, D, Koh, M, Lee, MW, Lim, D, Kim, MJ, Kim, YH, Cho, WJ, Lee, CH, Park, SB, Koo, S-H & Choi, HS 2012, 'Orphan nuclear receptor estrogen-related receptor γ(ERRγ) is key regulator of hepatic gluconeogenesis', Journal of Biological Chemistry, vol. 287, no. 26, pp. 21628-21639. https://doi.org/10.1074/jbc.M111.315168
Kim, Don Kyu ; Ryu, Dongryeol ; Koh, Minseob ; Lee, Min Woo ; Lim, Donghyun ; Kim, Min Jung ; Kim, Yong Hoon ; Cho, Won Jea ; Lee, Chul Ho ; Park, Seung Bum ; Koo, Seung-Hoi ; Choi, Hueng Sik. / Orphan nuclear receptor estrogen-related receptor γ(ERRγ) is key regulator of hepatic gluconeogenesis. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 26. pp. 21628-21639.
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