GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease

Autor(en)
Anja Baumann, Katharina Burger, Raphaela Staltner, Finn Jung, Dragana Rajcic, Maria José Lorenzo Pisarello, Annette Brandt, Ina Bergheim
Abstrakt

Background and aims

Insulin resistance is among the key risk factors for the development of non-alcoholic fatty liver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisome proliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2 diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanisms involved.
Methods

Female C57BL/6J mice were pair-fed either a liquid control diet (C) or a fat-, fructose- and cholesterol-rich diet (FFC) for 8 weeks while either being treated with GW9662 (1 mg/kg body weight; C+GW9662 and FFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parameters of glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challenged J774A.1 cells were treated with 10 μM GW9662.
Results

Despite similar caloric intake the development of NAFLD and insulin resistance were significantly attenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels in portal plasma were almost similarly increased in both FFC-fed groups while expressions of toll-like receptor 4 (Tlr4), myeloid differentiation primary response 88 (Myd88) and interleukin 1 beta (Il1b) as well as nitrite (NO2−) concentration in liver were significantly higher in FFC-fed mice than in FFC+GW9662-treated animals. In J774A.1 cells, treatment with GW9662 significantly attenuated LPS-induced expression of Il1b, interleukin 6 (Il6) and inducible nitric oxide synthase (iNos) as well as NO2− formation.
Conclusion

In summary, our data suggest that the PPARγ antagonist GW9662 attenuates the development of a diet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signaling cascade.

Organisation(en)
Department für Ernährungswissenschaften
Journal
Metabolism
Band
133
ISSN
0026-0495
DOI
https://doi.org/10.1016/j.metabol.2022.155233
Publikationsdatum
05-2022
Peer-reviewed
Ja
ÖFOS 2012
303009 Ernährungswissenschaften
Schlagwörter
ASJC Scopus Sachgebiete
Endocrinology, Endocrinology, Diabetes and Metabolism
Link zum Portal
https://ucrisportal.univie.ac.at/de/publications/gw9662-a-peroxisome-proliferatoractivated-receptor-gamma-antagonist-attenuates-the-development-of-nonalcoholic-fatty-liver-disease(70ae0cd9-b1cd-44dd-94bf-50097ee42951).html