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 P Graham; Harmeet Malhi

doi:10.1111/hepr.13052

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

Hepatol Res. 2018 May;48(6):479-494. doi: 10.1111/hepr.13052. Epub 2018 Feb 9.

Authors

Harikrishna Bandla¹, Debanjali Dasgupta¹, Amy S Mauer¹, Barbora Nozickova², Swarup Kumar³, Petra Hirsova¹, Rondell P Graham⁴, Harmeet Malhi¹

Affiliations

¹ Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
² Institute of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
³ Department of Medicine, Saint Vincent Hospital, Worcester, Massachusetts, USA.
⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.

Abstract

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.

Keywords: endoplasmic reticulum stress; fatty liver; hepatocyte apoptosis.

Abstract

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