Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis. NAFLD is closely linked to obesity, insulin resistance and dyslipidemia. AMP-activated protein kinase (AMPK) functions as an energy sensor and plays a central role in regulating lipid metabolism. In this study, we identified a series of novel pyrazolone AMPK activators using a homogeneous time-resolved fluorescence assay (HTRF) based on the AMPKα2β1γ1 complex. Compound 29 (C29) is a candidate compound that directly activated the kinase domain of AMPK with an EC50 value of 2.1-0.2 μmol/L and acted as a non-selective activator of AMPK complexes. Treatment of HepG2 cells with C29 (20, 40 μmol/L) dose-dependently inhibited triglyceride accumulation. Chronic administration of C29 (10, 30 mg/kg every day, po, for 5 weeks) significantly improved lipid metabolism in both the liver and the plasma of ob/ob mice. These results demonstrate that the AMPK activators could be part of a novel treatment approach for NAFLD and associated metabolic disorders.

中文翻译：

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新型取代的吡唑啉酮衍生物作为AMP激活的蛋白激酶激活剂，可抑制脂质合成并减少ob / ob小鼠的脂质蓄积。

非酒精性脂肪肝疾病（NAFLD）是一种以肝脂肪变性为特征的临床综合征。NAFLD与肥胖，胰岛素抵抗和血脂异常密切相关。AMP激活的蛋白激酶（AMPK）充当能量传感器，并在调节脂质代谢中发挥重要作用。在这项研究中，我们使用基于AMPKα2β1γ1复合物的均相时间分辨荧光测定法（HTRF）鉴定了一系列新型吡唑啉酮AMPK激活剂。化合物29（C29）是一种候选化合物，可以直接激活AMPK的激酶结构域，EC50值为2.1-0.2μmol/ L，并充当AMPK复合物的非选择性激活剂。用C29（20，40μmol/ L）处理HepG2细胞剂量依赖性地抑制了甘油三酸酯的积累。长期服用C29（每天10次，每次30 mg / kg，口服，持续5周）可显着改善ob / ob小鼠肝脏和血浆中的脂质代谢。这些结果表明AMPK激活剂可能是NAFLD和相关代谢紊乱的新型治疗方法的一部分。