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

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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 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
JournalGastroenterology
Volume135
Issue number6
DOIs
Publication statusPublished - Dec 2008

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ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Sinclair, E. M., Yusta, B., Streutker, C., Baggio, L. L., Koehler, J., Charron, M. J., & Drucker, D. J. (2008). Glucagon Receptor Signaling Is Essential for Control of Murine Hepatocyte Survival. Gastroenterology, 135(6), 2096-2106. https://doi.org/10.1053/j.gastro.2008.07.075