| First Author | Rao J | Year | 2015 |
| Journal | Biochem J | Volume | 466 |
| Issue | 2 | Pages | 369-78 |
| PubMed ID | 25387528 | Mgi Jnum | J:221389 |
| Mgi Id | MGI:5639000 | Doi | 10.1042/BJ20140412 |
| Citation | Rao J, et al. (2015) C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1alpha signalling in acute liver failure. Biochem J 466(2):369-78 |
| abstractText | 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 (ERO1alpha), 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 ERO1alpha, 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 ERO1alpha. In contrast, CHOP deficiency decreased hepatocellular apoptosis/necrosis and increased animal survival. Furthermore, disruption of CHOP decreased ERO1alpha expression leading to reducing ROS-induced cell death in vivo and in vitro. Interestingly, ERO1alpha 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 ERO1alpha, a key mediator to link ER stress and ROS. Therefore, targeting CHOP/ERO1alpha signalling could be a novel therapeutic approach during ALF. |
