Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies.

Humans Female Male Mice Animals Necroptosis Epigenesis, Genetic Non-alcoholic Fatty Liver Disease / genetics Hepatocytes Receptor-Interacting Protein Serine-Threonine Kinases / genetics Protein Kinases / genetics
Cell Death Chronic Infection NASH Necroptosis RIPK3

Journal

Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630

Informations de publication

Date de publication:
12 2022
Historique:
received: 13 09 2021
revised: 15 08 2022
accepted: 16 08 2022
pubmed: 30 8 2022
medline: 23 11 2022
entrez: 29 8 2022
Statut: ppublish

Résumé

Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology. Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes. Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis. We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

Sections du résumé

BACKGROUND & AIMS
Necroptosis is a highly inflammatory mode of cell death that has been implicated in causing hepatic injury including steatohepatitis/ nonalcoholic steatohepatitis (NASH); however, the evidence supporting these claims has been controversial. A comprehensive, fundamental understanding of cell death pathways involved in liver disease critically underpins rational strategies for therapeutic intervention. We sought to define the role and relevance of necroptosis in liver pathology.
METHODS
Several animal models of human liver pathology, including diet-induced steatohepatitis in male mice and diverse infections in both male and female mice, were used to dissect the relevance of necroptosis in liver pathobiology. We applied necroptotic stimuli to primary mouse and human hepatocytes to measure their susceptibility to necroptosis. Paired liver biospecimens from patients with NASH, before and after intervention, were analyzed. DNA methylation sequencing was also performed to investigate the epigenetic regulation of RIPK3 expression in primary human and mouse hepatocytes.
RESULTS
Identical infection kinetics and pathologic outcomes were observed in mice deficient in an essential necroptotic effector protein, MLKL, compared with control animals. Mice lacking MLKL were indistinguishable from wild-type mice when fed a high-fat diet to induce NASH. Under all conditions tested, we were unable to induce necroptosis in hepatocytes. We confirmed that a critical activator of necroptosis, RIPK3, was epigenetically silenced in mouse and human primary hepatocytes and rendered them unable to undergo necroptosis.
CONCLUSIONS
We have provided compelling evidence that necroptosis is disabled in hepatocytes during homeostasis and in the pathologic conditions tested in this study.

Identifiants

DOI: 10.1053/j.gastro.2022.08.040 PMID: 36037995
pubmed: 36037995
pii: S0016-5085(22)01021-6
doi: 10.1053/j.gastro.2022.08.040
pii:
doi:

Substances chimiques

RIPK3 protein, human EC 2.7.11.1
Receptor-Interacting Protein Serine-Threonine Kinases EC 2.7.11.1
MLKL protein, human EC 2.7.-
Protein Kinases EC 2.7.-
Ripk3 protein, mouse EC 2.7.11.1
MLKL protein, mouse EC 2.7.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1643-1657.e14

Commentaires et corrections

Type : CommentIn

Informations de copyright

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Auteurs

Simon P Preston (SP)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Michael D Stutz (MD)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Cody C Allison (CC)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Ueli Nachbur (U)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Quentin Gouil (Q)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Bang Manh Tran (BM)

Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia.

Valerie Duvivier (V)

Cardiovascular and Metabolic Disease Center for Therapeutic Innovation, SERVIER Group, Suresnes, France.

Philip Arandjelovic (P)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

James P Cooney (JP)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Liana Mackiewicz (L)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Yanxiang Meng (Y)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Jan Schaefer (J)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Stefanie M Bader (SM)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Hongke Peng (H)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Zina Valaydon (Z)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Pravin Rajasekaran (P)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Charlie Jennison (C)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Sash Lopaticki (S)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.

Ann Farrell (A)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Marno Ryan (M)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Jess Howell (J)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Catherine Croagh (C)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Denuja Karunakaran (D)

Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia; Monash Biomedicine Discovery Institute and Victorian Heart Institute, Monash University, Clayton, Victoria, Australia.

Carole Schuster-Klein (C)

Cardiovascular and Metabolic Disease Center for Therapeutic Innovation, SERVIER Group, Suresnes, France.

James M Murphy (JM)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Theodora Fifis (T)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Christopher Christophi (C)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Elizabeth Vincan (E)

Department of Infectious Diseases, The University of Melbourne, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Victorian Infectious Disease Reference Laboratory, The Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia; Curtin Medical School, Curtin University, Perth, Western Australia, Australia.

Marnie E Blewitt (ME)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Alexander Thompson (A)

Department of Gastroenterology, St. Vincent's Hospital, The University of Melbourne, Melbourne, Victoria, Australia.

Justin A Boddey (JA)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia.

Marcel Doerflinger (M)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: doerflinger.m@wehi.edu.au.

Marc Pellegrini (M)

Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia. Electronic address: Pellegrini@wehi.edu.au.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Eucaryotes › Animaux › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Nécroptose › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Phénomènes génétiques › Régulation de l'expression des gènes › Épigenèse génétique › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › Stéatose hépatique non alcoolique › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Receptor-Interacting Protein Serine-Threonine Kinases › Epigenetic Silencing of RIPK3 in Hepatocytes...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Phosphotransferases (Alcohol Group Acceptor) › Protein kinases › Epigenetic Silencing of RIPK3 in Hepatocytes...