C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure
C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure
复制标题
C/EBP 同源蛋白 (CHOP) 在急性肝衰竭中通过促进 ERO1α 信号传导导致肝细胞死亡。
DOI：
10.1042/bj20140412
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发表时间：
2015-03-01
影响因子：
4.1
通讯作者：
Zhang, Feng
中科院分区：
文献类型：
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作者：
Rao, Jianhua;Zhang, Chuangyong;Zhang, Feng
CCAAT/增强子结合蛋白(C/EBP)-同源蛋白（CHOP）已被证明是内质网（ER）应激介导的细胞凋亡的关键分子。ER氧化还原蛋白1- α (ERO1 α)是CHOP的靶标，是一种重要的氧化酶，可调节活性氧（ROS），在急性肝衰竭（ALF）时肝细胞死亡中发挥重要作用。然而，对于CHOP如何促进ros诱导的肝细胞损伤，我们知之甚少。本研究旨在探讨CHOP在ALF中的作用及其分子机制。在ALF患者的肝组织中，CHOP的表达显著增加，同时与健康对照相比，dsrna依赖性蛋白激酶（PKR）样ER激酶（PERK）信号、激活转录因子4 （ATF6）信号、肌醇要求酶-1 （IRE1）信号和ERO1 α的表达增加。在半乳糖胺(GaIN)/脂多糖（LPS）诱导的ALF小鼠模型中，肝细胞损伤伴随着PERK信号、ATF6信号、IRE1信号、CHOP和ERO1 α的上调。相反，CHOP缺乏可减少肝细胞凋亡/坏死，提高动物存活率。此外，CHOP的破坏降低了体内和体外ros诱导的细胞死亡，从而减少了ERO1 α的表达。有趣的是，在chop缺陷小鼠中，过表达的ERO1 α恢复了GaIN/ lps诱导的肝细胞损伤。我们的研究首次证明CHOP通过激活er1 α来促进ALF期间的肝损伤，er1 α是连接内质网应激和ROS的关键介质。因此，靶向CHOP/ERO1 α信号可能是ALF的一种新的治疗方法。
CCAAT/enhancer binding protein (C/EBP)-homologous protein (CHOP) has been shown to be a key molecule in endoplasmic reticulum (ER) stress-mediated apoptosis. ER oxidoreductin 1-alpha (ERO1 alpha), a target of CHOP, is an important oxidizing enzyme that regulates reactive oxygen species (ROS), which play a prominent role in hepatocellular death during acute liver failure (ALF). However, little is known about how CHOP facilitates ROS-induced hepatocellular injury. The present study was designed to investigate the roles and molecular mechanisms of CHOP in ALF. In the liver tissues from ALF patients, the expression of CHOP was significantly increased, which was accompanied by increased expression of dsRNA-dependent protein kinase (PKR)-like ER kinase (PERK) signalling, activating transcription factor 4 (ATF6) signalling, inositol-requiring enzyme-1 (IRE1) signalling and ERO1 alpha, as compared with healthy controls. In the mousemodel of galactosamine (GaIN)/lipopolysaccharide (LPS)-induced ALF, the hepatocellular injury was accompanied by up-regulated PERK signalling, ATF6 signalling, IRE1 signalling, CHOP and ERO1 alpha. In contrast, CHOP deficiency decreased hepatocellular apoptosis/necrosis and increased animal survival. Furthermore, disruption of CHOP decreased ERO1 alpha expression leading to reducing ROS-induced cell death in vivo and in vitro. Interestingly, ERO1 alpha overexpression restored GaIN/LPS-induced hepatocellular injury in CHOP-deficient mice. Our studies demonstrate for the first time that CHOP promotes liver damage during ALF through activation of ERO1 alpha, a key mediator to link ER stress and ROS. Therefore, targeting CHOP/ERO1 alpha signalling could be a novel therapeutic approach during ALF.