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

Activation of the endoplasmic reticulum stress sensor PERK is a feature of nonalcoholic steatohepatitis (NASH), yet regulators of PERK signaling remain undefined in this context. P58 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 in the pathogenesis of dietary NASH. parameters of hepatocyte cell death, liver injury, inflammation, fibrosis, indirect calorimetry and PERK activation were assessed in p58 knockout (p58 ) mice and their wildtype littermate controls fed a diet enriched in Fat, Fructose, and Cholesterol (FFC) for 20 weeks. PERK activation was attenuated in FFC-fed p58 mice. Accordingly, FFC-fed p58 mice demonstrated 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 mice. we have demonstrated that in an in vivo dietary NASH model p58 mediates hepatocyte apoptosis and liver injury, likely via PERK phosphorylation. In the absence of p58 , PERK phosphorylation and NASH are attenuated. Inhibition of hepatic p58 may be a future target for NASH therapy.