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

Hai Wang, Miaoyun Zhao, Neetu Sud, Patricia Christian, Jing Shen, Yongyan Song, Anjeza Pashaj, Kezhong Zhang, Timothy Carr, Qiaozhu Su

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)
235 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)1-11
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 01 Sep 2016

Keywords

  • Animals
  • Cell Line, Tumor
  • Cyclic AMP/metabolism
  • Cyclic AMP Response Element-Binding Protein/genetics
  • Fatty Liver/genetics
  • Glucagon/pharmacology
  • Hep G2 Cells
  • Hepatocytes/drug effects
  • Humans
  • Hypertriglyceridemia/genetics
  • Lipid Metabolism/drug effects
  • Lipogenesis/drug effects
  • Membrane Proteins/genetics
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction/drug effects
  • Sterol Regulatory Element Binding Protein 1/genetics

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