State Key Laboratory of Drug Research, the National Drug Screening Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
University of Chinese Academy of Sciences, Beijing, 100049, China.
Acta Pharmacol Sin. 2018 Oct;39(10):1622-1632. doi: 10.1038/aps.2017.186. Epub 2018 May 24.
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.
非酒精性脂肪性肝病 (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) 作为能量传感器发挥作用，在调节脂质代谢中起着核心作用。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，它以 2.1-0.2 μmol/L 的 EC50 值直接激活 AMPK 的激酶结构域，并作为 AMPK 复合物的非选择性激活剂。用 C29（20、40 μmol/L）处理 HepG2 细胞可剂量依赖性地抑制甘油三酯的积累。C29（每天 10、30 mg/kg，po，连续 5 周）的慢性给药可显著改善 ob/ob 小鼠肝脏和血浆中的脂质代谢。这些结果表明，AMPK 激活剂可能成为治疗 NAFLD 及相关代谢紊乱的新方法的一部分。
