NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition.

Autor:	Vesting AJ; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Jais A; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG), 04103 Leipzig, Germany., Klemm P; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Steuernagel L; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Wienand P; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Fog-Tonnesen M; Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark., Hvid H; Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark., Schumacher AL; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany., Kukat C; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany., Nolte H; Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany., Georgomanolis T; University of Cologne, Cologne Center for Genomics, Cologne, Germany., Altmüller J; University of Cologne, Cologne Center for Genomics, Cologne, Germany., Pasparakis M; Institute for Genetics, University of Cologne, 50674 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Schmidt A; Institute for Genetics, University of Cologne, 50674 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Krüger M; Institute for Genetics, University of Cologne, 50674 Cologne, Germany, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany, Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany., Supprian MS; Institute of Experimental Hematology, TranslaTUM, Klinikum rechts der Isar der Technischen Universität München, 81675 Munich, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ) 69120 Heidelberg, Germany., Waisman A; Institute for Molecular Medicine, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Straub BK; Institute of Pathology, University Medical Centre of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Raschzok N; General, Visceral, and Transplantation Surgery, Charité-University School of Medicine, 13353 Berlin, Germany- Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Surgery, Experimental Surgery, Campus Charité Mitte | Campus Virchow-Klinikum, Berlin, Germany and Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Academy, Clinician Scientist Program, Berlin, Germany., Bernier M; Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA., Birkenfeld AL; Internal Medicine IV, Clinic of Diabetology, Endocrinology, Nephrology, Internal medicine IV, University Hospital and Faculty of Medicine of the Eberhard Karls University Tübingen, 72016 Tübingen, Germany and Institute of Diabetes Research and Metabolic Diseases, Helmholtz Zentrum München an der Uniklinik Tübingen, Deutsches Zentrum für Diabetesforschung (DZD), Germany., Hövelmeyer N; Institute for Molecular Medicine, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany., Brüning JC; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Wunderlich FT; Max Planck Institute for Metabolism Research, Gleueler Strasse 50, 50931 Cologne, Germany, Center for Endocrinology, Diabetes and Preventive Medicine (CEDP), University Hospital Cologne, Kerpener Strasse 26, 50924 Cologne, Germany, Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany. Electronic address: Thomas.wunderlich@sf.mpg.de.
Jazyk:	angličtina
Zdroj:	Molecular metabolism [Mol Metab] 2022 Dec; Vol. 66, pp. 101626. Date of Electronic Publication: 2022 Nov 07.
DOI:	10.1016/j.molmet.2022.101626
Abstrakt:	Objective: Nonalcoholic fatty liver disease (NAFLD) ranges from steatosis to nonalcoholic steatohepatitis (NASH), which often progresses to hepatocellular carcinoma (HCC) through a largely undefined mechanism. NASH and HCC depend on inflammatory signaling, whose master regulator is the NFκB transcription factor family, activated by canonical and non-canonical pathways. Methods: Here, we investigated non-canonical NFκB-inducing kinase (NIK/MAP3K14) in metabolic NASH, NASH to HCC transition, and DEN-induced HCC. To this end, we performed dietary and chemical interventions in mice that were analyzed via single nucleus sequencing, gene expression and histochemical methods. Ultimately, we verified our mouse results in human patient samples. Results: We revealed that hepatocyte-specific NIK deficiency (NIKLKO) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NFκB pathway. Instead, hepatic NIK attenuated hepatoprotective JAK2/STAT5 signaling that is a prerequisite for NASH and NASH to HCC progression in mice and humans. Conclusions: Our data suggest NIK-mediated inhibitory JAK2 phosphorylation at serine 633 that might be amenable for future therapeutic interventions in patients. (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.)
Databáze:	MEDLINE
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