The strength of the Fas ligand signal determines whether hepatocytes act as type 1 or type 2 cells in murine livers.
The BH3-interacting domain death agonist Bid has been shown to be critical for Fas-induced hepatocellular apoptosis. Furthermore, some studies have suggested that phosphorylation of Bid may determine its apoptotic function and may act as a switch to nonapoptotic functions. The aim of this study was to evaluate the role of Bid and phosphorylated Bid for Fas ligand (FasL)-induced apoptosis in murine livers. The monoclonal antibody Jo2 and a hexameric form of sFasL (MegaFasL) were used to induce apoptosis in wild-type, Bid-deficient (Bid(-/-)), Bid transgenic mice expressing a nonphosphorable form of Bid and Fas receptor-deficient lpr mice. Apoptosis sensitivity was determined in healthy mice and in mice following bile duct ligation, partial hepatectomy, or suramin pretreatment. As previously reported, loss of Bid protects mice against Jo2-induced liver failure. Remarkably however, Bid(-/-) mice are highly sensitive to MegaFasL-induced apoptosis. MegaFasL-treated Bid(-/-) mice showed a typical type I cell signaling behavior with activation of caspase-3 without Bax translocation to the mitochondria and no cytochrome C/Smac release into the cytosol. In contrast to previous in vitro findings, phosphorylation of Bid does not affect the sensitivity of hepatocytes to Fas receptor-mediated apoptosis in vivo.


CONCLUSIONS
Our data suggest that Bid mainly amplifies a weak death receptor signal in quiescent and nonquiescent hepatocytes rendering the liver more sensitive to FasL-induced apoptosis. Thus, depending on the efficacy of Fas receptor activation, hepatocytes and nonparenchymal cells can either behave as type I or type II cells.
Schüngel
Sven
S
Clinic of Hepatology, Gastroenterology and Endocrinology, Hannover Medical School, Hannover, Germany.
Buitrago-Molina
Laura Elisa
LE
Nalapareddy
Padmavathi devi
Pd
Lebofsky
Margitta
M
Manns
Michael P
MP
Jaeschke
Hartmut
H
Gross
Atan
A
Vogel
Arndt
A
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis / Q000502:physiology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000235:genetics / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000378:metabolism*; D006498:Hepatectomy / Q000009:adverse effects; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology*; D008026:Ligation / Q000009:adverse effects; D008099:Liver / Q000378:metabolism* / Q000473:pathology*; D017093:Liver Failure / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051023:BH3 Interacting Domain Death Agonist Protein; C494815:Bid protein, mouse; D053222:Fas Ligand Protein; D019014:fas Receptor; D020169:Caspases