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Author Notes:

Address Correspondence and Reprint Requests to: Nitika Arora Gupta, M.D., D.C.H., D.N.B. Associate Professor of Pediatrics 1760 Haygood Drive Atlanta, GA 30322 E‐mail:nitika.gupta@emory.edu' Tel.: +1‐404‐727‐2026

Acknowledgment: We are thankful to V. Dixit and Kim Newton (Roche, CA) for RIPK3–/– mice, R. Hakem (University of Toronto) for mice with CAPS8fl/fl allele, RIPK1‐K45A mice were provided by Dr. John Bertin (Glaxo‐Smith‐Klein), BID–/– mice were kindly provided by A. Strasser (The Walter and Eliza Hall Institute of Medical Research, Australia).

We acknowledge Emory Animal Physiology core, ICI core, CHOA and Winship Pathology core for their support.

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Research Funding:

National Institutes of Health. Grant Number: DK091506

NASPGHAN Foundation. Grant Number: AI065429

Influence of Fat on Differential Receptor Interacting Serine/Threonine Protein Kinase 1 Activity Leading to Apoptotic Cell Death in Murine Liver Ischemia Reperfusion Injury Through Caspase 8.

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Journal Title:

Hepatology Communications

Volume:

Volume 3, Number 7

Publisher:

, Pages 925-942

Type of Work:

Article | Final Publisher PDF

Abstract:

Current understanding is that receptor interacting serine/threonine protein kinase 1 (RIPK1) can lead to two distinct forms of cell death: RIPK3-mediated necroptosis or caspase 8 (Casp8)-mediated apoptosis. Here, we report that RIPK1 signaling is indispensable for protection from hepatocellular injury in a steatotic liver undergoing ischemia reperfusion injury (IRI) but not in the lean liver. In lean liver IRI, RIPK1-mediated cell death is operational, leading to protection in RIP1 kinase-dead knock-in (RIPK1K45A) mice and necrostatin-1s (Nec1s)-treated lean wild-type (WT) mice. However, when fed a high-fat diet (HFD), RIPK1K45A-treated and Nec1s-treated WT mice undergoing IRI demonstrate exacerbated hepatocellular injury along with decreased RIPK1 ubiquitylation. Furthermore, we demonstrate that HFD-fed RIPK3-/-/Casp8-/- mice show protection from IRI, but HFD-fed RIPK3-/-/Casp8-/+ mice do not. We also show that blockade of RIPK1 leads to increased Casp8 activity and decreases mitochondrial viability. Conclusion: Although more studies are required, we provide important proof of concept for RIPK1 inhibition leading to distinctive outcomes in lean and steatotic liver undergoing IRI. Considering the rising incidence of nonalcoholic fatty liver disease (NAFLD) in the general population, it will be imperative to address this critical difference when treating patients with RIPK1 inhibitors. This study also presents a new target for drug therapy to prevent hepatocellular injury in NAFLD.

Copyright information:

© 2019 The Authors. Hepatology Communications published by Wiley Periodicals, Inc., on behalf of the American Association for the Study of Liver Diseases.

This is an Open Access work distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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