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TAT-apoptosis repressor with caspase recruitment domain protein transduction rescues mice from fulminant liver failure

Item Type:Article
Title:TAT-apoptosis repressor with caspase recruitment domain protein transduction rescues mice from fulminant liver failure
Creators Name:An, J. and Harms, C. and Lättig-Tünnemann, G. and Sellge, G. and Mandic, A.D. and Malato, Y. and Heuser, A. and Endres, M. and Trautwein, C. and Donath, S.
Abstract:Acute liver failure (ALF) is associated with massive hepatocyte cell death and high mortality rates. Therapeutic approaches targeting hepatocyte injury in ALF are hampered by the activation of distinct stimulus-dependent pathways, mechanism of cell death and a limited therapeutic window. The apoptosis repressor with caspase recruitment domain (ARC) is a recently discovered death repressor that inhibits both death receptor and mitochondrial apoptotic signaling.Here, we investigated the in vivo effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on Fas- and TNF-mediated murine models of fulminant liver failure. Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by Fas-agonistic antibody (Jo2), concanavalin A (ConA) or D-galactosamine/lipopolysaccharide (GalN/LPS) administration. Importantly, survival of mice was even preserved when TAT-ARC therapy was initiated in a delayed manner after stimulation with Jo2, ConA or GalN/LPS. ARC blocked hepatocyte apoptosis by directly interacting with members of the death-inducing signaling complex. TNF-mediated liver damage was inhibited by two independent mechanisms, inhibtion of jun kinase (JNK)-mediated TNF{alpha} expression and prevention of hepatocyte apoptosis by inhibition of both death receptor and mitochondrial death signaling. We identified JNK as a novel target of ARC. ARC's CARD directly interacts with JNK1 and JNK2 which correlates with decreased JNK activation and JNK-dependent TNF{alpha}?production. Conclusion: This work suggests that ARC confers hepatoprotection upstream and at the hepatocyte level. The efficacy of TAT-ARC protein transduction in multiple murine models of ALF demonstrates its therapeutic potential for reversing liver failure.
Keywords:Liver Failure, ARC, Apoptosis, Tumor Necrosis Factor, JNK, Animals, Mice
Page Range:715-726
Date:August 2012
Official Publication:https://doi.org/10.1002/hep.25697
PubMed:View item in PubMed

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