Molecular Metabolism (Dec 2022)
NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition
- Anna Juliane Vesting,
- Alexander Jais,
- Paul Klemm,
- Lukas Steuernagel,
- Peter Wienand,
- Morten Fog-Tonnesen,
- Henning Hvid,
- Anna–Lena Schumacher,
- Christian Kukat,
- Hendrik Nolte,
- Theodoros Georgomanolis,
- Janine Altmüller,
- Manolis Pasparakis,
- Andreas Schmidt,
- Marcus Krüger,
- Marc Schmidt Supprian,
- Ari Waisman,
- Beate Katharina Straub,
- Nathanael Raschzok,
- Michel Bernier,
- Andreas L. Birkenfeld,
- Nadine Hövelmeyer,
- Jens C. Brüning,
- F. Thomas Wunderlich
Affiliations
- Anna Juliane Vesting
- 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
- Alexander Jais
- 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
- Paul Klemm
- 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
- Lukas Steuernagel
- 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
- Peter Wienand
- 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
- Morten Fog-Tonnesen
- Global Drug Discovery, Novo Nordisk A/S, Novo Nordisk Park 1, 2760 Maaloev, Denmark
- Henning Hvid
- Pathology & Imaging, Novo Nordisk A/S, Novo Nordisk Park 1, DK-2760 Maaloev, Denmark
- Anna–Lena Schumacher
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
- Christian Kukat
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
- Hendrik Nolte
- Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Str. 9b, 50931 Cologne, Germany
- Theodoros Georgomanolis
- University of Cologne, Cologne Center for Genomics, Cologne, Germany
- Janine Altmüller
- University of Cologne, Cologne Center for Genomics, Cologne, Germany
- Manolis Pasparakis
- 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
- Andreas Schmidt
- 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
- Marcus Krüger
- 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
- Marc Schmidt Supprian
- 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
- Ari Waisman
- Institute for Molecular Medicine, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Beate Katharina Straub
- Institute of Pathology, University Medical Centre of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Nathanael Raschzok
- 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
- Michel Bernier
- Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA
- Andreas L. Birkenfeld
- 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
- Nadine Hövelmeyer
- Institute for Molecular Medicine, Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany
- Jens C. Brüning
- 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
- F. Thomas Wunderlich
- 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; Corresponding author.
- Journal volume & issue
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Vol. 66
p. 101626
Abstract
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.
