Research Article Details

Article ID: A49739
PMID: 35654114
Source: Metabolism
Title: GW9662, a peroxisome proliferator-activated receptor gamma antagonist, attenuates the development of non-alcoholic fatty liver disease.
Abstract: 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.
DOI: 10.1016/j.metabol.2022.155233

Strategy ID Therapy Strategy Synonyms Therapy Targets Therapy Drugs
S01 Improve insulin resistance insulin sensitizer; insulin resistance; glucose tolerance Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide Details

Target ID Target Name GENE Action Class UniProtKB ID Entry Name
T09 Toll-like receptor 4 TLR4 antagonist Membrane receptor O00206 TLR4_HUMAN Details
T10 Caspase-1 CASP1 inhibitor Enzyme P29466 CASP1_HUMAN Details
T18 Acetyl-CoA carboxylase 1 ACACA inhibitor Enzyme Q13085 ACACA_HUMAN Details
T05 Peroxisome proliferator-activated receptor gamma PPARG agonist Nuclear hormone receptor P37231 PPARG_HUMAN Details

Diseases ID DO ID Disease Name Definition Class
I05 9352 Type 2 diabetes mellitus A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus Details

Drug ID Drug Name Type DrugBank ID Targets Category Latest Progress
D579 Emfilermin Miscellany -- adipocytes Enhance lipid metabolism Under investigation Details
D182 Insulin Biological drug DB00030 INSR agonist; CPE modulator&product of -- Under clinical trials Details
D142 Fructose Chemical drug DB04173 -- Intravenous nutrition drug Under clinical trials Details