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

Autor:	Amy S. Mauer, Harmeet Malhi, Swarup Kumar, Harikrishna Bandla, Rondell P. Graham, Debanjali Dasgupta, Petra Hirsova, Barbora Nozickova
Rok vydání:	2018
Předmět:	0301 basic medicine Liver injury endocrine system medicine.medical_specialty Programmed cell death Hepatology biology Chemistry Receptor expression Endoplasmic reticulum medicine.disease 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Infectious Diseases Endocrinology medicine.anatomical_structure Alanine transaminase Fibrosis 030220 oncology & carcinogenesis Internal medicine Hepatocyte medicine biology.protein Steatohepatitis
Zdroj:	Hepatology Research. 48:479-494
ISSN:	1386-6346
DOI:	10.1111/hepr.13052
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=doi_________::121d69be2f461062227b1199bc50e705 https://doi.org/10.1111/hepr.13052 Zobrazit plný text záznamu Plný text ve formátu PDF Plný text ve formátu HTML
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