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Vesting, A.J.* ; Jais, A. ; Klemm, P.* ; Steuernagel, L.* ; Wienand, P.* ; Fog-Tonnesen, M.* ; Hvid, H.* ; Schumacher, A.L.* ; Kukat, C.* ; Nolte, H.* ; Georgomanolis, T.* ; Altmüller, J.* ; Pasparakis, M.* ; Schmidt, A.* ; Krüger, M.* ; Supprian, M.S.* ; Waisman, A.* ; Straub, B.K.* ; Raschzok, N.* ; Bernier, M.* ; Birkenfeld, A.L. ; Hövelmeyer, N.* ; Brüning, J.C.* ; Wunderlich, F.T.*

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

Mol. Metab. 66:101626 (2022)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Nik In Nash To Hcc Progression ; Nik-mediated Jak2 Inhibition Impairs Stat5 Signaling; Nf-kappa-b; Hepatic Growth-hormone; Fatty Liver-disease; Tyrosine Kinase Jak2; Signal Transducer; Nonalcoholic Steatohepatitis; Protein-kinase; Phosphorylation; Activation; Expression
ISSN (print) / ISBN 2212-8778
e-ISSN 2212-8778
Journal Molecular Metabolism
Quellenangaben Volume: 66, Issue: , Pages: , Article Number: 101626 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Institute of Diabetes Research and Metabolic Diseases (IDM)
Grants Universität zu Köln
Novo Nordisk
National Institute on Aging
National Institutes of Health
CECAD