Deletion of endoplasmic reticulum stress-responsive co-chaperone p58^IPK protects mice from diet-induced steatohepatitis

Aim: Activation of PKR-like endoplasmic reticulum kinase (PERK), an endoplasmic reticulum stress sensor, is a feature of non-alcoholic steatohepatitis (NASH), yet regulators of PERK signaling remain undefined in this context. The protein p58^IPK regulates PERK; however, its role in NASH has not been examined. The aim of this study was to assess the in vivo role of p58^IPK in the pathogenesis of dietary NASH. Methods: Parameters of hepatocyte cell death, liver injury, inflammation, fibrosis, indirect calorimetry and PERK activation were assessed in p58^IPK knockout (p58^ipk−/−) mice and their wild-type littermate controls. All animals were fed a diet enriched in fat, fructose, and cholesterol (FFC) for 20 weeks. Results: Activation of PERK was attenuated in FFC-fed p58^ipk−/− mice. Accordingly, FFC-fed p58^ipk−/− mice showed a reduction in hepatocyte apoptosis and death receptor expression, with a significant reduction in serum alanine transaminase values. Correspondingly, macrophage accumulation and fibrosis were significantly lower in FFC-fed p58^ipk−/− mice. Conclusion: We have shown that, in an in vivo dietary NASH model, p58^IPK mediates hepatocyte apoptosis and liver injury, likely through PERK phosphorylation. In the absence of p58^IPK, PERK phosphorylation and NASH are attenuated. Inhibition of hepatic p58^IPK could be a future target for NASH therapy.