Glucagon receptor signaling is essential for control of murine hepatocyte survival.
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.
Sinclair
Elaine M
EM
Department of Medicine, Mt. Sinai Hospital, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada.
Yusta
Bernardo
B
Streutker
Catherine
C
Baggio
Laurie L
LL
Koehler
Jacqueline
J
Charron
Maureen J
MJ
Drucker
Daniel J
DJ
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*
D005765:Gastrointestinal Agents; D018027:Receptors, Glucagon; D012313:RNA; D005934:Glucagon