Journal
HEPATOLOGY RESEARCH
Volume 48, Issue 6, Pages 479-494Publisher
WILEY
DOI: 10.1111/hepr.13052
Keywords
endoplasmic reticulum stress; fatty liver; hepatocyte apoptosis
Categories
Funding
- National Institute of Diabetes and Digestive and Kidney Disease [DK 97178, DK107402, DK111378]
- Robert and Elizabeth Strickland Career Development Award from Division of Endocrinology of the Mayo Foundation for Medical Education and Research
- Gilead Sciences Research Scholars Program in Liver Disease
- Palumbo Foundation
- Edward C. Kendall Research Fellowship Award of the Mayo Foundation for Medical Education and Research
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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 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.
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