Deletion of endoplasmic reticulum stress-responsive co-chaperone p58IPK protects mice from diet-induced steatohepatitis

Harikrishna Bandla, Debanjali Dasgupta, Amy S. Mauer, Barbora Nozickova, Swarup Kumar, Petra Hirsova, Rondell Graham, Harmeet M Malhi

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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 p58IPK regulates PERK; however, its role in NASH has not been examined. The aim of this study was to assess the in vivo role of p58IPK in the pathogenesis of dietary NASH. Methods: Parameters of hepatocyte cell death, liver injury, inflammation, fibrosis, indirect calorimetry and PERK activation were assessed in p58IPK knockout (p58ipk-/-) 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 p58ipk-/- mice. Accordingly, FFC-fed p58ipk-/- 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 p58ipk-/- mice. Conclusion: We have shown that, in an in vivo dietary NASH model, p58IPK mediates hepatocyte apoptosis and liver injury, likely through PERK phosphorylation. In the absence of p58IPK, PERK phosphorylation and NASH are attenuated. Inhibition of hepatic p58IPK could be a future target for NASH therapy.

Original languageEnglish (US)
JournalHepatology Research
StateAccepted/In press - Jan 1 2018



  • Endoplasmic reticulum stress
  • Fatty liver
  • Hepatocyte apoptosis

ASJC Scopus subject areas

  • Hepatology
  • Infectious Diseases

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