Type I neuregulin1\u03b1 is a novel local mediator to suppress hepatic gluconeogenesis in mice

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

doi:10.1038/srep42959

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.

Highlights

Schizophrenia[7,8,9]
We have demonstrated that the type I isoform of NRG1 with an α-type EGF-like domain (NRG1α) suppresses hepatic glucose production, in part, by activating both the AKT and ERK signalling cascades and subsequently inhibiting FoxO1-mediated gluconeogenic gene expression
Two distinct types of Nrg[1], Type I Nrg1α and Type III Nrg1β, were predominantly detected in the liver by PCR (Fig. 1 and Supplementary Fig. S1). Repeated sequencing of the latter isoform revealed that exon sequences encoding its N-terminal domain were not identical to those reported in the brain[16] and lacked the final 70 nucleotides of exon 1, introducing premature stop codons in the EGF-like domain of Type III Nrg1β

Summary

Introduction

Schizophrenia[7,8,9]. NRG1 stimulates glucose uptake by translocating the glucose transporter and increases insulin sensitivity in skeletal muscles[10,11], indicating that it is regulator of glucose metabolism. NRG1β2 shows the same blood glucose-lowering effects by stimulating ERBB3-AKT-FoxO1 signalling cascade and subsequently inhibiting hepatic gluconeogenesis in diabetic mice[14] These observations indicate that NRG1 has important roles in the regulation of systemic glucose metabolism by activating the ERBB3-mediated signalling pathways, little information is available on which Nrg[1] isoforms are expressed in the liver and their functions as a local mediator of hepatic glucose metabolism. We have demonstrated that the type I isoform of NRG1 with an α-type EGF-like domain (NRG1α) suppresses hepatic glucose production, in part, by activating both the AKT and ERK signalling cascades and subsequently inhibiting FoxO1-mediated gluconeogenic gene expression These results suggest that NRG1αacts as a local regulator of liver gluconeogenesis in an autocrine/paracrine manner

Methods

Results

Conclusion