Delayed-Onset Caspase-Dependent Massive Hepatocyte Apoptosis upon Fas Activation in Bak/Bax-Deficient Mice
Delayed-Onset Caspase-Dependent Massive Hepatocyte Apoptosis upon Fas Activation in Bak/Bax-Deficient Mice
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DOI：
10.1002/hep.24305
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发表时间：
2011-07-01
期刊：
影响因子：
13.5
通讯作者：
Hayashi, Norio
中科院分区：
文献类型：
--
作者：
Hikita, Hayato;Takehara, Tetsuo;Hayashi, Norio
促凋亡的Bcl2家族蛋白Bak和Bax是线粒体凋亡途径的重要通道。当被BH3蛋白激活时，Bak/Bax触发线粒体外膜通透性，导致细胞色素c的释放，然后激活启动子，然后激活效应器caspase来分解细胞。肝细胞通常被认为是II型细胞，因为据报道，当Fas受到刺激时，它们需要BH3-Only蛋白BID来进行凋亡。然而，Bak和Bax在肝脏中的意义尚不清楚。为了解决这个问题，我们建立了肝细胞特异性的Bald Bax双基因敲除小鼠，并给它们注射了Jo2激动型抗Fas抗体或重组Fas配体。Bak基因敲除小鼠的Fas诱导的快速暴发性肝细胞凋亡在Bak基因敲除小鼠中得到部分改善，而在Bax基因敲除小鼠中未见改善，而在双基因敲除小鼠中在注射Jo2后3h完全消失。重要的是，在6小时后，双基因敲除小鼠表现出严重的肝损伤，伴随着XIAP的抑制，caspase-3/7的激活和肝脏中寡核体DNA的断裂，没有证据表明线粒体的破坏或依赖细胞色素c的caspase-9的激活。在亲环素D基因敲除的背景下，这种肝损伤没有改善，也不能通过给予Necrostatin-1来改善，但在Bid裂解后给予caspase抑制剂完全抑制。结论：虽然Bak或Bax是Fas介导的肝脏大规模细胞凋亡快速发生所必需的，但即使两者都不存在，线粒体非依赖性、caspase依赖性的细胞凋亡也会延迟发生。这项研究揭示了一种外在的凋亡途径，就像在I型细胞中一样，它甚至在II型细胞中也是一个备份系统。(《肝病》2011；54：240-251)
The proapoptotic Bcl-2 family proteins Bak and Bax serve as an essential gateway to the mitochondrial pathway of apoptosis. When activated by BH3-only proteins, Bak/Bax triggers mitochondrial outer membrane permeabilization leading to release of cytochrome c followed by activation of initiator and then effector caspases to dismantle the cells. Hepatocytes are generally considered to be type II cells because, upon Fas stimulation, they are reported to require the BH3-only protein Bid to undergo apoptosis. However, the significance of Bak and Bax in the liver is unclear. To address this issue, we generated hepatocyte-specific Bald Bax double knockout mice and administered Jo2 agonistic anti-Fas antibody or recombinant Fas ligand to them. Fas-induced rapid fulminant hepatocyte apoptosis was partially ameliorated in Bak knockout mice but not in Bax knockout mice, and was completely abolished in double knockout mice 3 hours after Jo2 injection. Importantly, at 6 hours, double knockout mice displayed severe liver injury associated with repression of XIAP, activation of caspase-3/7 and oligonucleosomal DNA breaks in the liver, without evidence of mitochondrial disruption or cytochrome c dependent caspase-9 activation. This liver injury was not ameliorated in a cyclophilin D knockout background nor by administration of necrostatin-1, but was completely inhibited by administration of a caspase inhibitor after Bid cleavage. Conclusion: Whereas either Bak or Bax is critically required for rapid execution of Fas-mediated massive apoptosis in the liver, delayed onset of mitochondria-independent, caspase-dependent apoptosis develops even in the absence of both. The present study unveils an extrinsic pathway of apoptosis, like that in type I cells, which serves as a backup system even in type II cells. (HEPATOLOGY 2011;54:240-251)