Hepatocellular RECK as a Critical Regulator of Metabolic Dysfunction-Associated Steatohepatitis Development.

MASH MASLD NAFLD NASH amphiregulin epidermal growth factor receptor extracellular matrix fatty liver disease reversion inducing cysteine rich protein with kazal motifs steatosis

Journal

Cellular and molecular gastroenterology and hepatology
ISSN: 2352-345X
Titre abrégé: Cell Mol Gastroenterol Hepatol
Pays: United States
ID NLM: 101648302

Informations de publication

Date de publication:
24 May 2024
Historique:
received: 15 08 2023
revised: 17 05 2024
accepted: 20 05 2024
medline: 27 5 2024
pubmed: 27 5 2024
entrez: 26 5 2024
Statut: aheadofprint

Résumé

REversion inducing Cysteine rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood. We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis. Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild type mice. Hepatocyte-RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (A Disintegrin And Metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation. Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlight its potential as a novel therapeutic in MASH.

Sections du résumé

BACKGROUND AND AIMS OBJECTIVE
REversion inducing Cysteine rich protein with Kazal motifs (RECK) is an extracellular matrix regulator with anti-fibrotic effects. However, its expression and role in metabolic dysfunction-associated steatohepatitis (MASH) and hepatic fibrosis are poorly understood.
METHODS METHODS
We generated a novel transgenic mouse model with RECK overexpression specifically in hepatocytes to investigate its role in Western diet (WD)-induced liver disease. Proteomic analysis and in vitro studies were performed to mechanistically link RECK to hepatic inflammation and fibrosis.
RESULTS RESULTS
Our results show that RECK expression is significantly decreased in liver biopsies from human patients diagnosed with MASH and correlated negatively with severity of metabolic dysfunction-associated steatotic liver disease (MASLD) and fibrosis. Similarly, RECK expression is downregulated in WD-induced MASH in wild type mice. Hepatocyte-RECK overexpression significantly reduced hepatic pathology in WD-induced liver injury. Proteomic analysis highlighted changes in extracellular matrix and cell-signaling proteins. In vitro mechanistic studies linked RECK induction to reduced ADAM10 (A Disintegrin And Metalloproteinase domain-containing protein 10) and ADAM17 activity, amphiregulin release, epidermal growth factor receptor activation, and stellate cell activation.
CONCLUSION CONCLUSIONS
Our in vivo and mechanistic in vitro studies reveal that RECK is a novel upstream regulator of inflammation and fibrosis in the diseased liver, its induction is hepatoprotective, and thus highlight its potential as a novel therapeutic in MASH.

Identifiants

DOI: 10.1016/j.jcmgh.2024.101365 PMID: 38797477
pubmed: 38797477
pii: S2352-345X(24)00119-X
doi: 10.1016/j.jcmgh.2024.101365
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101365

Informations de copyright

Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.

Auteurs

Ryan J Dashek (RJ)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; NextGen Precision Health, University of Missouri, Columbia, MO, 65211; Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, 65211; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211. Electronic address: dashekr@umsystem.edu.

Rory P Cunningham (RP)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211. Electronic address: rorycunningham78@gmail.com.

Christopher L Taylor (CL)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; NextGen Precision Health, University of Missouri, Columbia, MO, 65211; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211. Electronic address: clt29p@missouri.edu.

Isabella Alessi (I)

Department of Surgery, University of Missouri, Columbia, MO, 65211. Electronic address: ialessi@jcmg.org.

Connor Diaz (C)

School of Medicine, University of Missouri, Columbia, MO, 65211. Electronic address: cgdvgv@health.missouri.edu.

Grace M Meers (GM)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; NextGen Precision Health, University of Missouri, Columbia, MO, 65211; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211. Electronic address: meersg@health.missouri.edu.

Andrew A Wheeler (AA)

Department of Surgery, University of Missouri, Columbia, MO, 65211. Electronic address: wheeleraa@health.missouri.edu.

Jamal A Ibdah (JA)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, 65211. Electronic address: ibdahj@health.missouri.edu.

Elizabeth J Parks (EJ)

NextGen Precision Health, University of Missouri, Columbia, MO, 65211; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, 65211. Electronic address: parksej@missouri.edu.

Tadashi Yoshida (T)

Department of Medicine and Physiology, School of Medicine, Tulane University, New Orleans, LA 70112. Electronic address: tyoshida@tulane.edu.

Bysani Chandrasekar (B)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; Division of Cardiology, Department of Medicine, University of Missouri, Columbia, MO, 65211; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, 65211; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, MO, 65211, United States of America. Electronic address: chandrasekarb@health.missouri.edu.

R Scott Rector (RS)

Research Service, Harry S Truman Memorial Veterans Medical Center, Columbia, MO 65212; NextGen Precision Health, University of Missouri, Columbia, MO, 65211; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, MO, 65211; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, MO, 65211. Electronic address: rectors@health.missouri.edu.

Classifications MeSH