C/EBP homologous protein (CHOP) contributes to hepatocyte death via the promotion of ERO1α signalling in acute liver failure

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.