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

ANJA BAUMANN; KATHARINA BURGER; ANNETTE BRANDT; RAPHAELA STALTNER; FINN JUNG; DRAGANA RAJCIC; MARIA JOSE LORENZO PISARELLO; INA BERGHEIM

Metabolism: Clinical and Experimental

W.B. Saunders

Año: 2022 vol. 133

Insulin resistance is among the key risk factors for the development of non-alcoholic fattyliver disease (NAFLD). Recently, it has been reported that GW9662, shown to be a potent peroxisomeproliferator-activated receptor gamma (PPARγ) antagonist, may improve insulin sensitivity in settings of type 2diabetes. Here, we determined the effects of GW9662 on the development of NAFLD and molecular mechanismsinvolved.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 andFFC+GW9662) or vehicle (C and FFC) i.p. three times weekly. Indices of liver damage and inflammation, parametersof glucose metabolism and portal endotoxin levels were determined. Lipopolysaccharide (LPS)-challengedJ774A.1 cells were treated with 10 μM GW9662.Results: Despite similar caloric intake the development of NAFLD and insulin resistance were significantlyattenuated in FFC+GW9662-treated mice when compared to FFC-fed animals. Bacterial endotoxin levels inportal 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. InJ774A.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 adiet-induced NAFLD and that this is associated with a protection against the activation of the TLR4 signalingcascade.