C/EBPα alleviates hepatic ischemia‐reperfusion injury by inhibiting endoplasmic reticulum stress via HDAC1‐mediated deacetylation of ATF4

Abstract Hepatic ischemia‐reperfusion (IR) injury is a complex systemic process causing a series clinical problem. C/EBPα is a key transcription factor for hepatocyte function, but its role and mechanism in regulating hepatic IR injury are largely unknown. Occluding portal vein and hepatic artery was used to establish a mouse model of hepatic IR injury. C/EBPα expression was decreased in IR‐injured liver compared with the sham, accompanied by increased contents of serum alanine transaminase (ALT), aspartate transaminase (AST), high mobility group box‐1, and proportion of hepatic cells. Oxygen and glucose deprivation/recovery (OGD/R) was used to establish a cellular hepatic IR model in WRL‐68 hepatocytes in vitro, and C/EBPα was overexpressed in the hepatocytes to evaluate its effect on hepatic IR injury. OGD/R promoted oxidative stress, cell apoptosis and endoplasmic reticulum (ER) stress in hepatocytes, which was reversed by C/EBPα overexpression. Then, we found that C/EBPα promoted histone deacetylase 1 (HDAC1) transcription through binding to HDAC1 promoter. Moreover, HDAC1 deacetylated the activating transcription factor 4 (ATF4), a key positive regulator of ER stress. Trichostatin‐A (an HDAC inhibitor) or ATF4 overexpression reversed the improvement of C/EBPα on OGD/R‐induced ER stress and hepatocyte dysfunction. 4‐Phenylbutyric acid (an endoplasmic reticulum stress inhibitor) also reversed the hepatic IR injury induced by ATF4 overexpression. Finally, lentivirus‐mediated C/EBPα overexpression vector was applied to administrate hepatic IR mice, and the results showed that C/EBPα overexpression ameliorated IR‐induced hepatic injury, manifesting with reduced ALT/AST, oxidative stress and ER stress. Altogether, our findings suggested that C/EBPα ameliorated hepatic IR injury by inhibiting ER stress via HDAC1‐mediated deacetylation of ATF4 promoter.