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Hohenester, S.* ; Kanitz, V.* ; Schiergens, T.* ; Einer, C. ; Nagel, J.* ; Wimmer, R.* ; Reiter, F.P.* ; Gerbes, A.L.* ; de Toni, E.N.* ; Bauer, C.* ; Holdt, L.* ; Mayr, D.* ; Rust, C.* ; Schnurr, M.* ; Zischka, H. ; Geier, A.* ; Denk, G.*

IL-18 but not IL-1 signaling is pivotal for the initiation of liver injury in murine non-alcoholic fatty liver disease.

Int. J. Mol. Sci. 21:8602 (2020)
Verlagsversion Forschungsdaten DOI
Open Access Gold
Creative Commons Lizenzvertrag
Non-alcoholic fatty liver disease (NAFLD) is rising in prevalence, and a better pathophysiologic understanding of the transition to its inflammatory phenotype (NASH) is key to the development of effective therapies. To evaluate the contribution of the NLRP3 inflammasome and its downstream effectors IL-1 and IL-18 in this process, we applied the true-to-life “American lifestyle-induced obesity syndrome” (ALiOS) diet mouse model. Development of obesity, fatty liver and liver damage was investigated in mice fed for 24 weeks according to the ALiOS protocol. Lipidomic changes in mouse livers were compared to human NAFLD samples. Receptor knockout mice for IL-1 and IL-18 were used to dissect the impact of downstream signals of inflammasome activity on the development of NAFLD. The ALiOS diet induced obesity and liver steatosis. The lipidomic changes closely mimicked changes in human NAFLD. A pro-inflammatory gene expression pattern in liver tissue and increased serum liver transaminases indicated early liver damage in the absence of histological evidence of NASH. Mechanistically, Il-18r−/−-but not Il-1r−/− mice were protected from early liver damage, possibly due to silencing of the pro-inflammatory gene expression pattern. Our study identified NLRP3 activation and IL-18R-dependent signaling as potential modulators of early liver damage in NAFLD, preceding development of histologic NASH.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Alios ; Inflammasome ; Interleukin 1 ; Interleukin 18 ; Nafld ; Nash ; Nlrp3 ; Western Diet; Acid Compositions; Scoring System; Tissue; Nafld; Steatohepatitis; Inflammasomes; Mitochondria; Progression; Steatosis; Fructose
ISSN (print) / ISBN 1422-0067
e-ISSN 1661-6596
Quellenangaben Band: 21, Heft: 22, Seiten: , Artikelnummer: 8602 Supplement: ,
Verlag MDPI
Verlagsort Basel
Begutachtungsstatus
Förderungen Eli Lilly and Company
Berlin Mathematical School
Faculty of Medicine, Munich University of Technology
Ludwig-Maximilians-Universitat Munchen