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Hildebrandt, X.* ; Veli, Ö.* ; Hyoubi, A.* ; Zinngrebe, J.* ; Abdallah, A.T.* ; Rodefeld, J.* ; Hoffmann, A. ; Gardeweg, L.* ; Kaya, Ö.* ; Wagner, E.* ; Lindhorst, A.* ; Poggenberg, M.* ; Wang, Y.* ; Dimmler, J.* ; Schillings, J.* ; Koci, P.* ; Bonechi, F.* ; Capuccino, L.V.* ; Kiefer, C.* ; Kelepouras, K.* ; Ghosh, A.* ; Noé, F.* ; Wolfrum, C.* ; Singer, M.* ; Liccardi, G.* ; Luedde, T.* ; Yavas, A.* ; Ghallab, A.* ; Hengsler, J.G.* ; Antczak, P.* ; Gericke, M.* ; Winkels, H.* ; Blüher, M. ; Walczak, H.* ; Annibaldi, A.* ; Fischer-Posovszky, P.* ; Peltzer, N.*

Linear ubiquitination prevents lipodystrophy and obesity-associated metabolic syndrome.

Sci. Adv. 11:eadw2539 (2025)
Verlagsversion Forschungsdaten DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Adipocyte hypertrophy during obesity triggers chronic inflammation, leading to metabolic disorders. However, the role of adipocyte-specific inflammatory signaling in metabolic syndrome remains unclear. The linear ubiquitin chain assembly complex, LUBAC, is an E3-ligase that generates nondegradative linear ubiquitination (Lin-Ub). LUBAC regulates NF-κB/MAPK-driven inflammation and prevents cell death triggered by immune receptors like TNF receptor-1. Here, we show that mice lacking HOIP, the Lin-E3 ligase catalytic subunit of LUBAC, in adipocytes (HoipA-KO) display lipodystrophy and heightened susceptibility to obesity-induced metabolic syndrome, particularly metabolic dysfunction-associated steatotic liver disease (MASLD). Mechanistically, loss of HOIP attenuates TNF-induced NF-κB activation and promotes cell death in human adipocytes. Inhibiting caspase-8-mediated cell death is sufficient to prevent lipodystrophy and MASLD in HoipA-KO obese mice. HOIP expression in adipose tissue positively correlates with metabolic fitness in obese individuals. Overall, our findings reveal a fundamental developmental role for Lin-Ub in adipocytes by mitigating cell death-driven adipose tissue inflammation and protecting against obesity-related metabolic syndrome.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Lipodystrophy; Adipose-tissue Inflammation; Insulin-resistance; Targeted Activation; Enrichment Analysis; Cell-death; Ikk-beta; Apoptosis; Fat; Mice; Expression
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Zeitschrift Science Advances
Quellenangaben Band: 11, Heft: 38, Seiten: , Artikelnummer: eadw2539 Supplement: ,
Verlag American Association for the Advancement of Science (AAAS)
Verlagsort Washington, DC [u.a.]
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
Förderungen Ministry of Science, Research and Arts Baden-Wuerttemberg (Margarete von Wrangell-Programm)
Deutsche Forschungsgemeinschaft
Jurgen Manchot Stiftung Foundation
Center of Mollecular Medicine of Cologne
Deutsches Zentrum fur Diabetesforschung