PuSH - Publication Server of Helmholtz Zentrum München

Export: TXT Text RIS Endnote (RIS) BIB BibTeX
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)
Publ. Version/Full Text Research data 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.
Impact Factor
Scopus SNIP
Altmetric
12.500
0.000
Tags
Annotations
Special Publikation
Hide on homepage

Edit extra information
Edit own tags
Private
Edit own annotation
Private
Hide on publication lists
on hompage
Mark as special
publikation
Publication type Article: Journal article
Document type Scientific Article
Keywords Lipodystrophy; Adipose-tissue Inflammation; Insulin-resistance; Targeted Activation; Enrichment Analysis; Cell-death; Ikk-beta; Apoptosis; Fat; Mice; Expression
Language english
Publication Year 2025
HGF-reported in Year 2025
ISSN (print) / ISBN 2375-2548
e-ISSN 2375-2548
Journal Science Advances
Quellenangaben Volume: 11, Issue: 38, Pages: , Article Number: eadw2539 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place Washington, DC [u.a.]
Reviewing status Peer reviewed
Institute(s) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF-Topic(s) 30201 - Metabolic Health
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-506501-001
Grants 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
DOI 10.1126/sciadv.adw2539
WOS ID 001574165300025
Scopus ID 105016673726
PubMed ID 40961178
Erfassungsdatum 2025-10-21
[➜Report correction]