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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Schattenberg, JM; Zimmermann, T; Wörns, M; Sprinzl, MF; Kreft, A; Kohl, T; Nagel, M; Siebler, J; Schulze Bergkamen, H; He, Y-W; Galle, PR; Schuchmann, M

Published Date

  • December 2011

Published In

Volume / Issue

  • 55 / 6

Start / End Page

  • 1272 - 1280

PubMed ID

  • 21703207

Pubmed Central ID

  • 21703207

Electronic International Standard Serial Number (EISSN)

  • 1600-0641

Digital Object Identifier (DOI)

  • 10.1016/j.jhep.2011.03.008

Language

  • eng

Conference Location

  • Netherlands