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.
- acute liver failure (ALF)
- C/EBP homologous protein (CHOP)
- endoplasmic reticulum (ER) stress
- endoplasmic reticulum oxidoreductin 1-α (ERO1α)
- reactive oxygen species (ROS)
Abbreviations: ATF, activating transcription factor; ALF, acute liver failure; BHA, butylated hydroxyanisole; CHOP, C/EBP homologous protein; CREB-2, cAMP response element binding protein 2; DMEM, Dulbecco's modified Eagle's medium; eIF2α, eukaryotic initiation factor α; ER, endoplasmic reticulum; ERO1α, endoplasmic reticulum oxidoreductin 1-α; GaIN, galactosamine; GPX-1, glutathione peroxidase 1; H&E, haematoxylin and eosin; HPRT, hypoxanthine phosphoribosyltransferase; IL-6, interleukin-6; IRE1, inositol-requiring enzyme-1; JNK, Jun N-terminal kinase; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; MDA, malondialdehyde; MPO, myeloperoxidase; NS, siRNA, non-specific siRNA; PDI, protein disulfide isomerase; PERK, PKR-like ER kinase; ROS, reactive oxygen species; RNS, reactive nitrogen species; sALT, serum alanine aminotransferase; sAST, serum aspartate aminotransferase; SOD, superoxide dismutase; TM, tunicamycin; TNF-α, tumour necrosis factor-α; TUNEL, terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling; UPR, unfolded protein response; WT, wild-type
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