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

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...

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Published in:Metabolism, clinical and experimental clinical and experimental, 2022-08, Vol.133, p.155233-155233, Article 155233
Main Authors: Baumann, Anja, Burger, Katharina, Brandt, Annette, Staltner, Raphaela, Jung, Finn, Rajcic, Dragana, Lorenzo Pisarello, Maria Jose, Bergheim, Ina
Format: Article
Language:English
Subjects:
Endotoxin
Glucose tolerance
Inflammation
Non-alcoholic steatohepatitis
Peroxisome proliferator-activated receptor gamma
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Summary: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. 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. 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. 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. [Display omitted] •Treatment with the PPARγ antagonist GW9662 protected against hepatic inflammation.•Treatment with the PPARγ antagonist GW9662 improved glucose tolerance.•Pparg2 was super-induced in livers of mice with diet-induced NAFLD.•The PPARγ antagonist GW9662 attenuated the induction of Pparg2 expression in liver.
ISSN:0026-0495
1532-8600
DOI:10.1016/j.metabol.2022.155233