Glucagon receptor signaling is essential for control of murine hepatocyte survival

Gastroenterology. 2008 Dec;135(6):2096-106. doi: 10.1053/j.gastro.2008.07.075. Epub 2008 Aug 3.

Abstract

Background & aims: Glucagon action in the liver is essential for control of glucose homeostasis and the counterregulatory response to hypoglycemia. Because receptors for the related peptides glucagon-like peptide-1 and glucagon-like peptide-2 regulate beta-cell and enterocyte apoptosis, respectively, we examined whether glucagon receptor (Gcgr) signaling modulates hepatocyte survival.

Methods: The importance of the Gcgr for hepatocyte cell survival was examined using Gcgr+/+ and Gcgr-/- mice in vivo, and murine hepatocyte cultures in vitro.

Results: Gcgr-/- mice showed enhanced susceptibility to experimental liver injury induced by either Fas Ligord activation or a methionine- and choline-deficient diet. Restoration of hepatic Gcgr expression in Gcgr-/- mice attenuated the development of hepatocellular injury. Furthermore, exogenous glucagon administration reduced Jo2-induced apoptosis in wild-type mice and decreased caspase activation in fibroblasts expressing a heterologous Gcgr and in primary murine hepatocyte cultures. The anti-apoptotic actions of glucagon were independent of protein kinase A, phosphatidylinositol-3K, and mitogen-activated protein kinase, and were mimicked by the exchange protein directly activated by the cyclic AMP agonist 8-(4-chloro-phenylthio)-2'-O-methyladenosine-3', 5'-cyclic monophosphate-cAMP.

Conclusions: These findings extend the essential actions of the Gcgr beyond the metabolic control of glucose homeostasis to encompass the regulation of hepatocyte survival.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis
  • Blotting, Western
  • Cell Survival
  • Cells, Cultured
  • Cricetinae
  • Disease Models, Animal
  • Electrophoresis, Polyacrylamide Gel
  • Gastrointestinal Agents / pharmacology
  • Gene Expression*
  • Glucagon / pharmacology
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology
  • Liver Failure / genetics*
  • Liver Failure / metabolism
  • Liver Failure / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • RNA / genetics*
  • Receptors, Glucagon / biosynthesis
  • Receptors, Glucagon / genetics*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Signal Transduction / genetics*

Substances

  • Gastrointestinal Agents
  • Receptors, Glucagon
  • RNA
  • Glucagon