Type i neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice

Takatomo Arai, Yumika Ono, Yujiro Arimura, Keimon Sayama, Tomohiro Suzuki, Satoko Shinjo, Mai Kanai, Shin Ichi Abe, Kentaro Senba, Nobuhito Goda

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Neuregulin1 is an epidermal growth factor (EGF)-like domain-containing protein that has multiple isoforms and functions as a local mediator in the control of various cellular functions. Here we show that type I isoform of neuregulin1 with an α-type EGF-like domain (Nrg1α) is the major isoform in mouse liver and regulates hepatic glucose production. Forced expression of Nrg1α in mouse liver enhanced systemic glucose disposal and decreased hepatic glucose production with reduced fasting blood glucose levels. Nuclear forkhead box protein O1 (FoxO1) and its downstream targets, PEPCK and G6Pase, were suppressed in liver and isolated hepatocytes by Nrg1α overexpression. In contrast, silencing of Nrg1α enhanced glucose production with increased PEPCK and G6Pase expressions in cAMP/dexamethasone-stimulated hepatocytes. Mechanistically, the recombinant α-type EGF-like domain of NRG1α (rNRG1α) stimulated the ERBB3 signalling pathway in hepatocytes, resulting in decreased nuclear FoxO1 accumulation via activation of both the AKT and ERK pathways. In addition, acute treatment with rNRG1α also suppressed elevation of blood glucose levels after both glucose and pyruvate challenge. Although a liver-specific deletion of Nrg1 gene in mice showed little effect on systemic glucose metabolism, these results suggest that NRG1α have a novel regulatory function in hepatic gluconeogenesis by regulating the ERBB3-AKT/ERK-FoxO1 cascade.

Original languageEnglish
Article number42959
JournalScientific Reports
Volume7
DOIs
Publication statusPublished - 2017 Feb 20

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Gluconeogenesis
Liver
Glucose
Epidermal Growth Factor
Hepatocytes
Protein Isoforms
Blood Glucose
MAP Kinase Signaling System
Gene Deletion
Nuclear Proteins
Pyruvic Acid
Dexamethasone
Fasting

ASJC Scopus subject areas

  • General

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Type i neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice. / Arai, Takatomo; Ono, Yumika; Arimura, Yujiro; Sayama, Keimon; Suzuki, Tomohiro; Shinjo, Satoko; Kanai, Mai; Abe, Shin Ichi; Senba, Kentaro; Goda, Nobuhito.

In: Scientific Reports, Vol. 7, 42959, 20.02.2017.

Research output: Contribution to journalArticle

Arai, Takatomo ; Ono, Yumika ; Arimura, Yujiro ; Sayama, Keimon ; Suzuki, Tomohiro ; Shinjo, Satoko ; Kanai, Mai ; Abe, Shin Ichi ; Senba, Kentaro ; Goda, Nobuhito. / Type i neuregulin1α is a novel local mediator to suppress hepatic gluconeogenesis in mice. In: Scientific Reports. 2017 ; Vol. 7.
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