Glucagon Receptor Signaling Is Essential for Control of Murine Hepatocyte Survival

Elaine M. Sinclair, Bernardo Yusta, Catherine Streutker, Laurie L. Baggio, Jacqueline Koehler, Maureen J. Charron, Daniel J. Drucker

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


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 β-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, phosphatioylinositol-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-methyladerosine-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.

Original languageEnglish (US)
Pages (from-to)2096-2106
Number of pages11
Issue number6
StatePublished - Dec 2008

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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