ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis
ARC is a novel therapeutic approach against acetaminophen-induced hepatocellular necrosis
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DOI：
10.1016/j.jhep.2012.10.002
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发表时间：
2013-02-01
影响因子：
25.7
通讯作者：
Donath, Stefan
中科院分区：
文献类型：
--
作者：
An, Junfeng;Mehrhof, Felix;Donath, Stefan
背景和目的：对乙酰氨基酚（AAP）过量是药物性肝衰竭的最常见原因。 c-Jun N 末端激酶 (JNK) 被认为在 MP 诱导的肝细胞坏死中发挥核心作用。具有半胱天冬酶募集结构域 (ARC) 的凋亡抑制因子是一种死亡抑制因子，可抑制死亡受体和线粒体凋亡信号传导。在这里，我们研究了ARC对AAP诱导的肝细胞坏死的治疗作用和分子机制。方法：我们测试了ARC与HIV-1转导结构域融合（TAT-ARC）对小鼠AAP肝毒性的体内和体外影响。结果：TAT-ARC蛋白治疗完全消除了C57BL/6小鼠中由AAP过量引起的致命性肝衰竭。 AAP 引发了不依赖于 caspase 的坏死，如肝脏组织学、血清转氨酶升高以及分泌被 ARC 抑制的 HMGB1 所证明。 ARC 介导的肝保护作用不是由 AAP 代谢的改变引起的，而是导致氧化应激减少。 AAP 过量导致 RIP 依赖性信号传导的诱导以及随后的 JNK 激活。异位 ARC 通过 ARC 与 JNK1 和 JNK2 之间的特异性相互作用抑制 INK 激活。重要的是，当 AAP 给药后延迟开始 ARC 治疗时，小鼠的存活甚至得以保留。结论：这项工作首次确定了 ARC-JNK 结合以及随后抑制 JNK 信号传导作为 ARC 干扰 AAP 依赖性坏死的特定机制。我们的数据表明 AAP 介导的 RIP 信号传导是肝细胞坏死的关键开关。 TAT-ARC 蛋白转导在小鼠 AAP 肝毒性中的功效表明其在人类中也具有逆转 AAP 中毒的治疗潜力。 (C) 2012 年欧洲肝脏研究协会。由 Elsevier B.V. 出版。保留所有权利。
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 MP-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 INK 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. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.