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-α (ERO1α), 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 ERO1α, as compared with healthy controls. In the mouse model of galactosamine (GaIN)/lipopolysaccharide (LPS)-induced ALF, the hepatocellular injury was accompanied by up-regulated PERK signalling, ATF6 signalling, IRE1 signalling, CHOP and ERO1α. In contrast, CHOP deficiency decreased hepatocellular apoptosis/necrosis and increased animal survival. Furthermore, disruption of CHOP decreased ERO1α expression leading to reducing ROS-induced cell death in vivo and in vitro. Interestingly, ERO1α 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 ERO1α, a key mediator to link ER stress and ROS. Therefore, targeting CHOP/ERO1α signalling could be a novel therapeutic approach during ALF.
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Research Article|
February 20 2015
C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure
Jianhua Rao;
Jianhua Rao
1
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Chuangyong Zhang;
Chuangyong Zhang
1
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Ping Wang;
Ping Wang
1
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Ling Lu;
Ling Lu
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Xiaofeng Qian;
Xiaofeng Qian
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Jianjie Qin;
Jianjie Qin
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Xiongxiong Pan;
Xiongxiong Pan
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Guoqiang Li;
Guoqiang Li
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Xuehao Wang;
Xuehao Wang
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
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Feng Zhang
Feng Zhang
2
*Liver Transplantation Center of First Affiliated Hospital and Translational Medicine Research Center of Jiangning Hospital, Nanjing Medical University, Nanjing 210029, People's Republic of China
2To whom correspondence should be addressed (email zhangf@njmu.edu.cn).
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Publisher: Portland Press Ltd
Received:
March 31 2014
Revision Received:
November 02 2014
Accepted:
November 11 2014
Accepted Manuscript online:
November 11 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 466 (2): 369–378.
Article history
Received:
March 31 2014
Revision Received:
November 02 2014
Accepted:
November 11 2014
Accepted Manuscript online:
November 11 2014
Citation
Jianhua Rao, Chuangyong Zhang, Ping Wang, Ling Lu, Xiaofeng Qian, Jianjie Qin, Xiongxiong Pan, Guoqiang Li, Xuehao Wang, Feng Zhang; C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure. Biochem J 1 March 2015; 466 (2): 369–378. doi: https://doi.org/10.1042/BJ20140412
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