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.

中文翻译：

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GW9662，一种过氧化物酶体增殖物激活受体 γ 拮抗剂，可减轻非酒精性脂肪肝的发展

背景和目标

胰岛素抵抗是非酒精性脂肪肝疾病 (NAFLD) 发展的关键风险因素之一。最近，据报道，GW9662 被证明是一种有效的过氧化物酶体增殖物激活受体 γ (PPARγ) 拮抗剂，可改善 2 型糖尿病患者的胰岛素敏感性。在这里，我们确定了 GW9662 对 NAFLD 发展的影响以及所涉及的分子机制。

方法

雌性 C57BL/6J 小鼠被配对喂养液体对照饮食 (C) 或富含脂肪、果糖和胆固醇的饮食 (FFC) 8 周，同时用 GW9662 (1 mg/kg 体重; C +GW9662 和 FFC+GW9662）或车辆（C 和 FFC）ip 每周 3 次。测定肝损伤和炎症指标、葡萄糖代谢参数和门静脉内毒素水平。用 10 μM GW9662 处理脂多糖 (LPS) 攻击的 J774A.1 细胞。

结果

尽管热量摄入相似，但与 FFC 喂养的动物相比，FFC+GW9662 治疗的小鼠的 NAFLD 和胰岛素抵抗的发展显着减弱。两个 FFC 喂养组的门静脉血浆中的细菌内毒素水平几乎同样增加，而 toll 样受体 4 ( Tlr4 )、骨髓分化初级反应 88 ( Myd88 ) 和白细胞介素 1 β ( Il1b ) 以及亚硝酸盐 (NO ₂ ^- ) FFC 喂养的小鼠肝脏中的浓度显着高于 FFC+GW9662 治疗的动物。在 J774A.1 细胞中，GW9662 处理显着减弱 LPS 诱导的Il1b、白细胞介素 6（Il6) 和诱导型一氧化氮合酶 ( iNos ) 以及 NO ₂ ^-的形成。

结论

总之，我们的数据表明 PPARγ 拮抗剂 GW9662 减弱了饮食诱导的 NAFLD 的发展，并且这与防止 TLR4 信号级联激活有关。