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ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis

Official URL:https://doi.org/10.1016/j.jhep.2012.10.002
PubMed:View item in PubMed
Creators Name:An, J. and Mehrhof, F. and Harms, C. and Laettig-Tuennemann, G. and Lee, S.L.L. and Endres, M. and Li, M. and Sellge, G. and Mandic, A.D. and Trautwein, C. and Donath, S.
Journal Title:Journal of Hepatology
Journal Abbreviation:J Hepatol
Volume:58
Number:2
Page Range:297-305
Date:February 2013
Keywords:ARC, Acetaminophen, JNK, Necrosis, Liver Failure, Animals, Mice
Abstract:Background & Aims: Acetaminophen (AAP) overdose is the most frequent cause of drug-induced liver failure. c-Jun N-terminal kinase (JNK) is thought to play a central role in AAP-induced hepatocellular necrosis. The apoptosis repressor with caspase recruitment domain (ARC) is a death repressor that inhibits death receptor and mitochondrial apoptotic signaling. Here, we investigated ARC's therapeutic effect and molecular mechanisms on AAP-induced hepatocellular necrosis. Methods: We tested the in vivo and in vitro effects of ARC fused with the transduction domain of HIV-1 (TAT-ARC) on murine AAP hepatotoxicity. Results: Treatment with TAT-ARC protein completely abrogated otherwise lethal liver failure induced by AAP overdose in C57BL/6 mice. AAP triggered caspase-independent necrosis, as evidenced by liver histology, elevated serum transaminases, and secreted HMGB1 that was inhibited by ARC. ARC-mediated hepatoprotection was not caused by an alteration of AAP metabolism, but resulted in reduced oxidative stress. AAP overdose led to induction of RIP-dependent signaling with subsequent JNK activation. Ectopic ARC inhibited JNK activation by specific interactions between ARC and JNK1 and JNK2. Importantly, survival of mice was even preserved when ARC therapy was initiated in a delayed manner after AAP administration. Conclusions: This work identifies for the first time ARC-JNK-binding with subsequent inhibition of JNK signaling as a specific mechanism of ARC to interfere with AAP-dependent necrosis. Our data suggests that AAP-mediated induction of RIP signaling serves as a critical switch for hepatocellular necrosis. The efficacy of TAT-ARC protein transduction in murine AAP hepatotoxicity suggests its therapeutic potential for reversing AAP intoxication also in humans.
ISSN:0168-8278
Publisher:Elsevier (The Netherlands)
Item Type:Article

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