Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis.

ADAM17 Protein / metabolism Animals Cell Line Chronic Disease Humans Liver / cytology Liver Cirrhosis / metabolism Macrophages / cytology Male Mice Mice, Inbred C57BL Mice, Knockout Non-alcoholic Fatty Liver Disease / metabolism Rats c-Mer Tyrosine Kinase / physiology
ADAM17 MerTK MerTK cleavage NASH TGFβ; hepatic stellate cells liver fibrosis macrophage nonalcoholic steatohepatitis retinoic acid

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
04 02 2020
Historique:
received: 15 05 2019
revised: 07 10 2019
accepted: 13 11 2019
pubmed: 17 12 2019
medline: 2 6 2021
entrez: 17 12 2019
Statut: ppublish

Résumé

Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis.

Identifiants

DOI: 10.1016/j.cmet.2019.11.013 PMID: 31839486 PMC: PMC7004886
pubmed: 31839486
pii: S1550-4131(19)30620-5
doi: 10.1016/j.cmet.2019.11.013
pmc: PMC7004886
mid: NIHMS1545589
pii:
doi:

Substances chimiques

MERTK protein, human EC 2.7.10.1
Mertk protein, mouse EC 2.7.10.1
c-Mer Tyrosine Kinase EC 2.7.10.1
ADAM17 Protein EC 3.4.24.86
ADAM17 protein, human EC 3.4.24.86

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

406-421.e7

Subventions

Organisme : NIDDK NIH HHS
ID : R56 DK068437
Pays : United States
Organisme : NIDDK NIH HHS
ID : K24 DK078772
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL120826
Pays : United States
Organisme : NIDDK NIH HHS
ID : R00 DK115778
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101251
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA212376
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL132412
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI089824
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK108370
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007343
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK116620
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK063608
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI136715
Pays : United States
Organisme : NIDDK NIH HHS
ID : K99 DK115778
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK068437
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL087123
Pays : United States
Organisme : NIDDK NIH HHS
ID : P30 DK034989
Pays : United States

Commentaires et corrections

Type : CommentIn
Type : CommentIn

Informations de copyright

Copyright © 2019 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.

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Auteurs

Bishuang Cai (B)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: bc2586@columbia.edu.

Paola Dongiovanni (P)

General Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.

Kathleen E Corey (KE)

Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA.

Xiaobo Wang (X)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Igor O Shmarakov (IO)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Ze Zheng (Z)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Canan Kasikara (C)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Viralkumar Davra (V)

Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School Cancer Center, Newark, NJ 07103, USA.

Marica Meroni (M)

General Medicine and Metabolic Diseases, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.

Raymond T Chung (RT)

Liver Center, Gastrointestinal Division, Massachusetts General Hospital, Boston, MA 02114, USA; Harvard Medical School, Boston, MA, USA.

Carla V Rothlin (CV)

Department of Immunobiology, Yale University School of Medicine and Department of Pharmacology, Yale University, New Haven, CT, USA.

Robert F Schwabe (RF)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University Irving Medical Center, New York, NY 10032, USA.

William S Blaner (WS)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA.

Raymond B Birge (RB)

Department of Microbiology, Biochemistry and Molecular Genetics, Rutgers University, New Jersey Medical School Cancer Center, Newark, NJ 07103, USA.

Luca Valenti (L)

Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milano 20122, Italy; Translational Medicine - Transfusion Medicine and Hematology, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano 20122, Italy.

Ira Tabas (I)

Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA; Departments of Pathology & Cell Biology and Physiology & Cellular Biophysics, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: iat1@columbia.edu.

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Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Glycoprotéines › Protéines ADAM › Protéine ADAM17 › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Maladie chronique › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Système digestif › Foie › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › Cirrhose du foie › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Systèmes sanguin et immunitaire › Système immunitaire › Phagocytes › Macrophages › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Souris transgéniques › Souris knockout › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Maladies de l'appareil digestif › Maladies du foie › Stéatose hépatique › Stéatose hépatique non alcoolique › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Macrophage MerTK Promotes Liver Fibrosis in...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines tumorales › Protéines oncogènes › Protéines proto-oncogènes › c-Mer Tyrosine kinase › Macrophage MerTK Promotes Liver Fibrosis in...