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