Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury.

Animals Chemical and Drug Induced Liver Injury Cytosol / metabolism Disease Models, Animal Hepatocytes / cytology Membrane Proteins / analysis Mice Protective Agents / metabolism Protective Factors
APAP MLKL RIPK3 drug-induced liver injury rhMG53

Journal

Journal of hepatology
ISSN: 1600-0641
Titre abrégé: J Hepatol
Pays: Netherlands
ID NLM: 8503886

Informations de publication

Date de publication:
03 2022
Historique:
received: 17 02 2021
revised: 20 09 2021
accepted: 18 10 2021
pubmed: 6 11 2021
medline: 1 3 2022
entrez: 5 11 2021
Statut: ppublish

Résumé

Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

Sections du résumé

BACKGROUND & AIMS
Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined.
METHODS
Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection.
RESULTS
Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation.
CONCLUSIONS
Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI.
LAY SUMMARY
Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

Identifiants

DOI: 10.1016/j.jhep.2021.10.017 PMID: 34736969
pubmed: 34736969
pii: S0168-8278(21)02154-1
doi: 10.1016/j.jhep.2021.10.017
pii:
doi:

Substances chimiques

MG53 protein, mouse 0
Membrane Proteins 0
Protective Agents 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

558-567

Subventions

Organisme : NIDDK NIH HHS
ID : R01 DK123475
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Déclaration de conflit d'intérêts

Conflict of interest JM and TT hold equity interest in TRIM-edicine, Inc. that develops MG53 for therapeutic applications. The Intellectual Properties related to MG53 are maintained by Rutgers University and The Ohio State University. All other authors declare that they have no competing interests. Please refer to the accompanying ICMJE disclosure forms for further details.

Auteurs

Yu Han (Y)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Sylvester Black (S)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Zhengfan Gong (Z)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Zhi Chen (Z)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Jae-Kyun Ko (JK)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Zhongshu Zhou (Z)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Tianyang Xia (T)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Dandong Fang (D)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Donghai Yang (D)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Daqian Gu (D)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Ziyue Zhang (Z)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Hongmei Ren (H)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China.

Xudong Duan (X)

Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China.

Brenda F Reader (BF)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Ping Chen (P)

Department of Hepatobiliary Surgery, Daping Hospital, Third Military Medical University, Chongqing, China.

Yongsheng Li (Y)

Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Jung-Lye Kim (JL)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Zhongguang Li (Z)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA; Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China.

Xuehong Xu (X)

Laboratory of Cell Biology, Genetics and Developmental Biology, Shannxi Normal University College of Life Sciences, Xi'an, China.

Li Guo (L)

Clinical Medicine Research Center, Xinqiao Hospital, Third Military Medical University, Chongqing, China.

Xinyu Zhou (X)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Erin Haggard (E)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Hua Zhu (H)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Tao Tan (T)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA.

Ken Chen (K)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China. Electronic address: ck_tmmu@sina.com.

Jianjie Ma (J)

Department of Surgery, Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH, USA. Electronic address: Jianjie.Ma@osumc.edu.

Chunyu Zeng (C)

Department of Cardiology, Daping Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory for Hypertension Research, Chongqing Cardiovascular Clinical Research Center, Chongqing Institute of Cardiology, Chongqing, PR China; State Key Laboratory of Trauma, Burns and Combined Injury, Daping Hospital, The Third Military Medical University, Chongqing, PR China; Cardiovascular Research Center of Chongqing College, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Chongqing, PR China. Electronic address: chunyuzeng01@163.com.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Troubles dus à des produits chimiques › Intoxication › Lésions hépatiques dues aux substances › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Cellules › Structures cellulaires › Fractions subcellulaires › Cytosol › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Cellules › Cellules épithéliales › Hépatocytes › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Actions chimiques et utilisations › Utilisations spécialisées de produits chimiques › Agents protecteurs › Membrane-delimited signaling and cytosolic...
questionsmedicales.fr › Environnement et santé publique › Santé publique › Méthodes épidémiologiques › Statistiques comme sujet › Probabilité › Risque › Facteurs de protection › Membrane-delimited signaling and cytosolic...