Glucagon regulates hepatic lipid metabolism via cAMP and Insig-2 signaling: implication for the pathogenesis of hypertriglyceridemia and hepatic steatosis

Authors

Hai Wang, University of Nebraska - LincolnFollow
Miaoyun Zhao, University of Nebraska-Lincoln
Neetu Sud, University of Nebraska-Lincoln
Patricia Christian, University of Nebraska-Lincoln
Jing Shen, University of Nebraska-Lincoln
Yongyan Song, University of Nebraska-Lincoln
Anjeza Pashaj, University of Nebraska-Lincoln
Kezhong Zhang, Wayne State University
Timothy P. Carr, University of Nebraska-LincolnFollow
Qiaozhu Su, University of Nebraska-LincolnFollow

Document Type

Article

Date of this Version

2016

Citation

Scientific Reports, 6:32246

Comments

This work is licensed under a Creative Commons Attribution 4.0 International License.

Abstract

Insulin induced gene-2 (Insig-2) is an ER-resident protein that inhibits the activation of sterol regulatory element-binding proteins (SREBPs). However, cellular factors that regulate Insig-2 expression have not yet been identified. Here we reported that cyclic AMP-responsive element-binding protein H (CREBH) positively regulates mRNA and protein expression of a liver specific isoform of Insig-2, Insig-2a, which in turn hinders SREBP-1c activation and inhibits hepatic de novo lipogenesis. CREBH binds to the evolutionally conserved CRE-BP binding elements located in the enhancer region of Insig-2a and upregulates its mRNA and protein expression. Metabolic hormone glucagon and nutritional fasting activated CREBH, which upregulated expression of Insig-2a in hepatocytes and inhibited SREBP-1c activation. In contrast, genetic depletion of CREBH decreased Insig-2a expression, leading to the activation of SREBP-1c and its downstream lipogenic target enzymes. Compromising CREBH-Insig-2 signaling by siRNA interference against Insig-2 also disrupted the inhibitory effect of this signaling pathway on hepatic de novo triglyceride synthesis. These actions resulted in the accumulation of lipid droplets in hepatocytes and systemic hyperlipidemia. Our study identified CREBH as the first cellular protein that regulates Insig-2a expression. Glucagon activated the CREBH-Insig-2a signaling pathway to inhibit hepatic de novo lipogenesis and prevent the onset of hepatic steatosis and hypertriglyceridemia.