Vesting, Anna Juliane, Jais, Alexander, Klemm, Paul, Steuernagel, Lukas ORCID: 0000-0003-0043-1436, Wienand, Peter, Fog-Tonnesen, Morten, Hvid, Henning, Schumacher, Anna-Lena, Kukat, Christian ORCID: 0000-0003-1508-0229, Nolte, Hendrik, Georgomanolis, Theodoros, Altmueller, Janine, Pasparakis', Manolis, Schmidt', Andreas, Krueger', Marcus, Supprian, Marc Schmidt, Waisman, Ari, Straub, Beate Katharina, Raschzok, Nathanael, Bernier, Michel, Birkenfeld, Andreas L. ORCID: 0000-0003-1407-9023, Hoevelmeyer, Nadine, Bruening, Jens C. and Wunderlich, F. Thomas (2022). NIK/MAP3K14 in hepatocytes orchestrates NASH to hepatocellular carcinoma progression via JAK2/STAT5 inhibition. Mol. Metab., 66. AMSTERDAM: ELSEVIER. ISSN 2212-8778

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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 NFKB transcription factor family, activated by canonical and non-canonical pathways. Methods: Here, we investigated non-canonical NFKB-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 hep-atocarcinogenesis, independent of its role in the NFKB 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.(c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Vesting, Anna JulianeUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jais, AlexanderUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klemm, PaulUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Steuernagel, LukasUNSPECIFIEDorcid.org/0000-0003-0043-1436UNSPECIFIED
Wienand, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fog-Tonnesen, MortenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hvid, HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schumacher, Anna-LenaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kukat, ChristianUNSPECIFIEDorcid.org/0000-0003-1508-0229UNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgomanolis, TheodorosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Altmueller, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pasparakis', ManolisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schmidt', AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Krueger', MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Supprian, Marc SchmidtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Waisman, AriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Straub, Beate KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raschzok, NathanaelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bernier, MichelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Birkenfeld, Andreas L.UNSPECIFIEDorcid.org/0000-0003-1407-9023UNSPECIFIED
Hoevelmeyer, NadineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bruening, Jens C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wunderlich, F. ThomasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-695002
DOI: 10.1016/j.molmet.2022.101626
Journal or Publication Title: Mol. Metab.
Volume: 66
Date: 2022
Publisher: ELSEVIER
Place of Publication: AMSTERDAM
ISSN: 2212-8778
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NF-KAPPA-B; HEPATIC GROWTH-HORMONE; FATTY LIVER-DISEASE; TYROSINE KINASE JAK2; SIGNAL TRANSDUCER; NONALCOHOLIC STEATOHEPATITIS; PROTEIN-KINASE; PHOSPHORYLATION; ACTIVATION; EXPRESSIONMultiple languages
Endocrinology & MetabolismMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69500

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