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

Autor:	Dashek RJ; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; NextGen Precision Health, University of Missouri, Columbia, Missouri; Department of Veterinary Pathobiology, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Cunningham RP; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Taylor CL; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; NextGen Precision Health, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Alessi I; Department of Surgery, University of Missouri, Columbia, Missouri., Diaz C; School of Medicine, University of Missouri, Columbia, Missouri., Meers GM; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; NextGen Precision Health, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri., Wheeler AA; Department of Surgery, University of Missouri, Columbia, Missouri., Ibdah JA; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri., Parks EJ; NextGen Precision Health, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri., Yoshida T; Department of Medicine and Physiology, School of Medicine, Tulane University, New Orleans, Louisiana., Chandrasekar B; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; Division of Cardiology, Department of Medicine, University of Missouri, Columbia, Missouri; Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri; Department of Medical Pharmacology and Physiology, University of Missouri, Columbia, Missouri., Rector RS; Research Service, Harry S. Truman Memorial Veterans Medical Center, Columbia, Missouri; NextGen Precision Health, University of Missouri, Columbia, Missouri; Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri; Division of Gastroenterology and Hepatology, Department of Medicine, University of Missouri, Columbia, Missouri. Electronic address: rectors@health.missouri.edu.
Jazyk:	angličtina
Zdroj:	Cellular and molecular gastroenterology and hepatology [Cell Mol Gastroenterol Hepatol] 2024; Vol. 18 (3), pp. 101365. Date of Electronic Publication: 2024 May 24.
DOI:	10.1016/j.jcmgh.2024.101365
Abstrakt:	Background & Aims: 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: 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: 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-specific 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: 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 highlights its potential as a novel therapeutic in MASH. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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