【摘 要】
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Non-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic steatosis.NAFLD is closely linked to obesity,insulin resistance and dy
【机 构】
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State Key Laboratory of Drug Research, the National Drug Screening Center, Shanghai Institute of Mat
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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.
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