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

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Item Type:Article
Title:NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition
Creators Name:Vesting, A.J. and Jais, A. and Klemm, P. and Steuernagel, L. and Wienand, P. and Fog-Tonnesen, M. and Hvid, H. and Schumacher, A.L. and Kukat, C. and Nolte, H. and Georgomanolis, T. and Altmüller, J. and Pasparakis, M. and Schmidt, A. and Krüger, M. and Supprian, M.S. and Waisman, A. and Straub, B.K. and Raschzok, N. and Bernier, M. and Birkenfeld, A.L. and Hövelmeyer, N. and Brüning, J.C. and Wunderlich, F.T.
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 NF?B transcription factor family, activated by canonical and non-canonical pathways. METHODS: Here, we investigated non-canonical NF?B-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 (NIK(LKO)) ameliorated metabolic NASH complications and reduced hepatocarcinogenesis, independent of its role in the NF?B 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.
Keywords:NIK in NASH to HCC Progression, NIK-Mediated JAK2 Inhibition Impairs STAT5 Signaling, Animals, Mice
Source:Molecular Metabolism
Page Range:101626
Date:December 2022
Official Publication:https://doi.org/10.1016/j.molmet.2022.101626
PubMed:View item in PubMed

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