Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice.
Receptor interacting protein kinase 3 is a critical early mediator of acetaminophen-induced hepatocyte necrosis in mice.
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DOI：
10.1002/hep.26547
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发表时间：
2013-12
期刊：
影响因子：
13.5
通讯作者：
Jaeschke, Hartmut
中科院分区：
文献类型：
--
作者：
Ramachandran, Anup;McGill, Mitchell R.;Xie, Yuchao;Ni, Hong-Min;Ding, Wen-Xing;Jaeschke, Hartmut
在美国，对乙酰氨基酚（APAP）过量是肝毒性和急性肝功能衰竭的主要原因，但其病理生理学尚不完全清楚。尽管有凋亡信号的证据，但APAP后的肝细胞死亡通常被认为是小鼠和人类的坏死。最近的研究结果表明，受体相互作用蛋白激酶3（RIP 3）作为一个开关，从凋亡到坏死（程序性坏死）。因此，目前研究的目的是确定RIP 3是否参与APAP诱导的肝细胞死亡。APAP（200-300 mg/kg）可引起C57 Bl/6 J小鼠谷胱甘肽耗竭和蛋白加合物形成、氧化应激、线粒体释放凋亡诱导因子和核DNA断裂，导致小叶中心坏死。在野生型动物或使用RIP 3缺陷小鼠中用反义吗啉抑制RIP 3蛋白诱导对蛋白加合物形成没有影响，但在APAP后6小时减弱了所有其他参数，包括坏死细胞死亡。此外，与野生型细胞相比，RIP 3缺陷小鼠的培养肝细胞在24小时后显示出减少的损伤。有趣的是，APAP诱导的线粒体转位的动力蛋白相关蛋白1（Drp 1），线粒体分裂的起始物，被抑制RIP 3蛋白表达和Drp 1抑制剂MDIVI减少APAP诱导的细胞死亡在24小时。在体内24 h或体外48 h后，这些保护作用均消失。结论：RIP 3是APAP肝毒性的早期介质，参与调节线粒体功能障碍和氧化应激。控制RIP 3表达可能是减少APAP诱导的肝损伤的一种有前途的新方法，但需要补充策略来控制线粒体功能障碍以实现长期保护。
Acetaminophen (APAP) overdose is a major cause of hepatotoxicity and acute liver failure in the US, but the pathophysiology is incompletely understood. Despite evidence for apoptotic signaling, hepatic cell death after APAP is generally considered necrotic in mice and in humans. Recent findings suggest that the receptor interacting protein kinase 3 (RIP3) acts as a switch from apoptosis to necrosis (programmed necrosis). Thus, the aim of the current investigation was to determine if RIP3 is involved in APAP-induced liver cell death. APAP (200–300 mg/kg) caused glutathione depletion and protein adduct formation, oxidant stress, mitochondrial release of apoptosis inducing factor, and nuclear DNA fragmentation resulting in centrilobular necrosis in C57Bl/6J mice. Inhibiting RIP3 protein induction with anti-sense morpholinos in wild-type animals or using RIP3-deficient mice had no effect on protein adduct formation but attenuated all other parameters, including necrotic cell death, at 6h after APAP. In addition, cultured hepatocytes from RIP3-deficient mice showed reduced injury compared to wild-type cells after 24h. Interestingly, APAP-induced mitochondrial translocation of dynamin-related protein 1 (Drp1), the initiator of mitochondrial fission, was inhibited by reduced RIP3 protein expression and the Drp1 inhibitor MDIVI reduced APAP-induced cell death at 24h. All of these protective effects were lost after 24h in vivo or 48h in vitro. Conclusion: RIP3 is an early mediator of APAP hepatotoxicity, involving modulation of mitochondrial dysfunction and oxidant stress. Controlling RIP3 expression could be a promising new approach to reduce APAP-induced liver injury, but requires complementary strategies to control mitochondrial dysfunction for long-term protection.
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影响因子：
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Park, B. Kevin
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