Ablation of c-FLIP in hepatocytes enhances death-receptor mediated apoptosis and toxic liver injury in vivo

J Hepatol. 2011 Dec;55(6):1272-80. doi: 10.1016/j.jhep.2011.03.008. Epub 2011 Apr 15.

Abstract

Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anthracenes / pharmacology
  • Apoptosis
  • CASP8 and FADD-Like Apoptosis Regulating Protein / deficiency*
  • CASP8 and FADD-Like Apoptosis Regulating Protein / genetics
  • Caspases / metabolism
  • Chemical and Drug Induced Liver Injury / metabolism*
  • Chemical and Drug Induced Liver Injury / pathology*
  • Concanavalin A / toxicity
  • Female
  • Galactosamine / toxicity
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Hepatocytes / pathology*
  • Lipopolysaccharides / toxicity
  • MAP Kinase Signaling System / drug effects
  • Mice
  • Mice, Knockout
  • Receptors, Death Domain / metabolism*
  • fas Receptor / agonists

Substances

  • Anthracenes
  • CASP8 and FADD-Like Apoptosis Regulating Protein
  • Cflar protein, mouse
  • Lipopolysaccharides
  • Receptors, Death Domain
  • fas Receptor
  • Concanavalin A
  • pyrazolanthrone
  • Galactosamine
  • Caspases