title: Glucagon receptor signaling is essential for control of murine hepatocyte survival.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Sinclair
authors.forename: Bernardo
authors.initials: B
authors.lastname: Yusta
authors.forename: Catherine
authors.initials: C
authors.lastname: Streutker
authors.forename: Laurie L
authors.initials: LL
authors.lastname: Baggio
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Koehler
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Charron
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Drucker
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002470:Cell Survival; D002478:Cells, Cultured; D006224:Cricetinae; D004195:Disease Models, Animal; D004591:Electrophoresis, Polyacrylamide Gel; D005765:Gastrointestinal Agents / Q000494:pharmacology; D015870:Gene Expression; D005934:Glucagon / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D017093:Liver Failure / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012313:RNA / Q000235:genetics*; D018027:Receptors, Glucagon / Q000096:biosynthesis / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
chemical_list: D005765:Gastrointestinal Agents; D018027:Receptors, Glucagon; D012313:RNA; D005934:Glucagon