title: Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo.
abstract: OBJECTIVE
  Apoptosis is crucially involved in acute and chronic liver injury, including viral, cholestatic, toxic, and metabolic liver disease. Additionally, dysregulation of apoptosis signaling pathways has been implicated in hepatocarcinogenesis. The most prominent members of the apoptosis-mediating tumor necrosis factor receptor superfamily are the TNF-R1 (CD120a) and the CD95 (Apo-1/Fas) receptor. Although extensively studied, the intracellular signaling events in hepatocytes are only incompletely understood.
  
  
  METHODS
  To examine the role of the caspase-8 homolog cellular FLICE-inhibitory protein (c-FLIP) in liver injury, we generated mice with hepatocyte specific deletion of c-FLIP. Three models of acute liver injury were employed: the agonistic anti-CD95 antibody Jo2, d-galactosamine and LPS (GalN/LPS), and concanavalin A.
  
  
  RESULTS
  Conditional ablation of c-FLIP in hepatocytes augmented liver injury and cell death in all three models of liver injury. CD95- and GalN/LPS-induced liver injury was ameliorated by a pancaspase inhibitor, while ConA-induced injury was unaffected by caspase inhibition. Augmented activation of the MAPK JNK was observed in parallel to liver injury in c-FLIP knockout mice in all injury models; however, inhibition of JNK only affected TNF- and ConA-mediated injury.
  
  
  CONCLUSIONS
  In summary, c-FLIP is a central regulator of cell death in hepatocytes, involving increased activation of caspases and the MAPK JNK.
authors.affiliation: Department of Medicine, University Medical Center, Johannes Gutenberg University, 55101 Mainz, Germany. schatten@uni-mainz.de
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schattenberg
authors.forename: Tim
authors.initials: T
authors.lastname: Zimmermann
authors.forename: Marcus
authors.initials: M
authors.lastname: Wörns
authors.forename: Martin F
authors.initials: MF
authors.lastname: Sprinzl
authors.forename: Andreas
authors.initials: A
authors.lastname: Kreft
authors.forename: Tobias
authors.initials: T
authors.lastname: Kohl
authors.forename: Michael
authors.initials: M
authors.lastname: Nagel
authors.forename: Jürgen
authors.initials: J
authors.lastname: Siebler
authors.forename: Henning
authors.initials: H
authors.lastname: Schulze Bergkamen
authors.forename: You-Wen
authors.initials: YW
authors.lastname: He
authors.forename: Peter R
authors.initials: PR
authors.lastname: Galle
authors.forename: Marcus
authors.initials: M
authors.lastname: Schuchmann
mesh_terms: D000818:Animals; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000172:deficiency* / Q000235:genetics; D020169:Caspases / Q000378:metabolism; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology*; D003208:Concanavalin A / Q000633:toxicity; D005260:Female; D005688:Galactosamine / Q000633:toxicity; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D008070:Lipopolysaccharides / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D053218:Receptors, Death Domain / Q000378:metabolism*; D019014:fas Receptor / Q000819:agonists
chemical_list: D000873:Anthracenes; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D008070:Lipopolysaccharides; D053218:Receptors, Death Domain; D019014:fas Receptor; D003208:Concanavalin A; C432165:pyrazolanthrone; D005688:Galactosamine; D020169:Caspases