C/EBP Homologous Protein (CHOP) Contributes to Hepatocyte Death Via the Promotion of ERO1α Signaling in Acute Liver Failure.

C/EBP Homologous Protein (CHOP) has been shown to be a key molecule in endoplasmic reticulum (ER) stress-mediated apoptosis. ERO1α, a target of CHOP, is an important oxidizing enzyme to regulate ROS, which play a prominent role in hepatocellular death during acute liver failure (ALF), but little is known regarding whether or how CHOP facilitates ROS-induced hepatocellular injury. This study was designed to investigate roles and mechanisms of CHOP in ALF. In the liver tissues from ALF patients, the expression of CHOP was significantly increased compared with healthy controls and was accompanied by increased expression of PERK, ATF4 and ERO1a. In the mouse model of GaIN/LPS-induced ALF, the hepatocellular injury was accompanied by upregulated CHOP and ERO1a. In contrast, CHOP deficiency decreased hepatocellular apoptosis/necrosis and increased animal survival. Furthermore, the disruption of CHOP decreased ERO1a expression, resulting in a reduction of ROS-induced cell death in vivo and in vitro. Interestingly, ERO1a overexpression restored GaIN/LPS induced hepatocellular injury in CHOP deletion mice. Our studies for the first time demonstrate CHOP promotes liver damage during ALF through ERO1a, which is a key molecule to link ER stress and ROS. Targeting CHOP or ERO1a may be a novel approach for the management of ALF.