Hepatocyte MMP14 mediates liver and inter-organ inflammatory responses to diet-induced liver injury.

Autor:	Kelly SC; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Higgins CB; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Sun J; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Adams JA; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Zhang Y; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA., Ballentine S; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA., Miao Y; Genome Engineering and Stem Cell Core, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA., Cui X; Genome Engineering and Stem Cell Core, McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO 63110, USA., Milewska M; Biotechnology Center, Silesian University of Technology, Krzywoustego 8, Gliwice 44-100, Poland.; Faculty of Chemistry, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland., Wandzik I; Biotechnology Center, Silesian University of Technology, Krzywoustego 8, Gliwice 44-100, Poland.; Faculty of Chemistry, Department of Organic Chemistry, Bioorganic Chemistry and Biotechnology, Silesian University of Technology, Krzywoustego 4, 44-100 Gliwice, Poland., Yoshino J; Department of Medicine, Keio University School of Medicine, Minato, Tokyo, Japan., Swarts BM; Department of Chemistry and Biochemistry, Central Michigan University, Mt. Pleasant, MI 48859, USA., Wada SI; Institute of Microbial Chemistry (BIKAKEN), Kamiosaki, Shinagawa-ku, Tokyo, 141-0021, Japan., DeBosch BJ; Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.; Department of Cell Biology & Physiology, Washington University School of Medicine, St. Louis, MO, USA.
Jazyk:	angličtina
Zdroj:	PNAS nexus [PNAS Nexus] 2024 Aug 30; Vol. 3 (9), pp. pgae357. Date of Electronic Publication: 2024 Aug 30 (Print Publication: 2024).
DOI:	10.1093/pnasnexus/pgae357
Abstrakt:	The matrix metalloproteinase MMP14 is a ubiquitously expressed, membrane-bound, secreted endopeptidase that proteolyzes substrates to regulate development, signaling, and metabolism. However, the spatial and contextual events inciting MMP14 activation and its metabolic sequelae are not fully understood. Here, we introduce an inducible, hepatocyte-specific MMP14-deficient model (MMP14 LKO mice) to elucidate cell-intrinsic and systemic MMP14 function. We show that hepatocyte MMP14 mediates diet-induced body weight gain, peripheral adiposity, and impaired glucose homeostasis and drives diet-induced liver triglyceride accumulation and induction of hepatic inflammatory and fibrotic gene expression. Single-nucleus RNA sequencing revealed that hepatocyte MMP14 mediates Kupffer cell and T-cell accumulation and promotes diet-induced hepatocellular subpopulation shifts toward protection against lipid absorption. MMP14 co-immunoprecipitation and proteomic analyses revealed MMP14 substrate binding across both inflammatory and cytokine signaling, as well as metabolic pathways. Strikingly, hepatocyte MMP14 loss-of-function suppressed skeletal muscle and adipose inflammation in vivo, and in a reductionist adipose-hepatocyte co-culture model. Finally, we reveal that trehalose-type glucose transporter inhibitors decrease hepatocyte MMP14 gene expression and nominate these inhibitors as translatable therapeutic metabolic agents. We conclude that hepatocyte MMP14 drives liver and inter-organ inflammatory and metabolic sequelae of obesogenic dietary insult. Modulating MMP14 activation and blockade thus represents a targetable node in the pathogenesis of hepatic inflammation. (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)
Databáze:	MEDLINE
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