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Journal Article

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

MPS-Authors
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Vesting,  Anna Juliane
Max Planck Institute for Metabolism Research, Obesity and Cancer, Group Wunderlich, Max Planck Society;

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Klemm,  Paul
Max Planck Institute for Metabolism Research, Brüning Group, Max Planck Society;

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Steuernagel,  Lukas
Max Planck Institute for Metabolism Research, Brüning Group, Max Planck Society;

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Wienand,  Peter
Max Planck Institute for Metabolism Research, Obesity and Cancer, Group Wunderlich, Max Planck Society;

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Brüning,  Jens Claus
Brüning – Neuronal Control of Metabolism, Department Brüning, Max Planck Institute for Metabolism Research, Max Planck Society;

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Wunderlich,  Frank Thomas
Wunderlich – Obesity and Cancer, Department Brüning, Max Planck Institute for Metabolism Research, Max Planck Society;

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Citation

Vesting, A. J., Jais, A., Klemm, P., Steuernagel, L., Wienand, P., Fog-Tonnesen, M., et al. (2022). NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition. Molecular Metabolism, 66: 101626. doi:10.1016/j.molmet.2022.101626.


Cite as: https://hdl.handle.net/21.11116/0000-000C-BCAE-D
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.