TY  - JOUR
A1  - Hohenester, Simon
A1  - Kanitz, Veronika
A1  - Schiergens, Tobias
A1  - Einer, Claudia
A1  - Nagel, Jutta
A1  - Wimmer, Ralf
A1  - Reiter, Florian P.
A1  - Gerbes, Alexander L.
A1  - De Toni, Enrico N.
A1  - Bauer, Christian
A1  - Holdt, Lesca
A1  - Mayr, Doris
A1  - Rust, Christian
A1  - Schnurr, Max
A1  - Zischka, Hans
A1  - Geier, Andreas
A1  - Denk, Gerald
T1  - IL-18 but not IL-1 signaling is pivotal for the initiation of liver injury in murine non-alcoholic fatty liver disease
JF  - International Journal of Molecular Sciences
N2  - 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.
KW  - NAFLD
KW  - Western diet
KW  - NLRP3
KW  - inflammasome
KW  - interleukin 1
KW  - interleukin 18
KW  - NASH
KW  - ALiOS
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-285221
SN  - 1422-0067
VL  - 21
IS  - 22
ER  -