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NSC48160 targets AMPKα to ameliorate nonalcoholic steatohepatitis by inhibiting lipogenesis and mitochondrial oxidative stress
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  • Jiaxin Zhang,
  • Xunzhe Yin,
  • Zuojia Liu,
  • Erkang Wang,
  • Jin Wang
Jiaxin Zhang
Chang Chun Institute of Applied Chemistry Chinese Academy of Sciences
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Xunzhe Yin
Changchun Institute of Applied Chemistry Chinese Academy of Sciences
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Zuojia Liu
Changchun Institute of Applied Chemistry Chinese Academy of Sciences

Corresponding Author:[email protected]

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Erkang Wang
Chang Chun Institute of Applied Chemistry Chinese Academy of Sciences
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Jin Wang
Stony Brook University
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Abstract

Background and Purpose: Hepatic steatosis, which is triggered by dysregulation of lipid metabolism and redox equilibrium in the liver, is regarded as a risk factor in the initiating process of NAFLD. However, pharmacologic engagement of this process appears to be difficult. This study aims to identify the target of NSC48160, and investigate the mechanism by which NSC48160 exerts its liver protecting effect and ameliorate nonalcoholic steatohepatitis. Experimental Approach: We identified the small molecule NSC48160 as an effective agent against nonalcoholic steatohepatitis. We found that NSC48160 significantly lowered hepatic lipid levels in vitro and in vivo by activating the AMPK-dependent pathway. Key Results: Here, we found that activation of liver AMPK by NSC48160 can prevent HFD-induced liver steatosis. RNA-seq profiling and metabonomics analysis revealed that NSC48160-induced lipogenesis is modulated by lipid metabolism. Using in silico molecular docking combined with surface plasmon resonance and cellular thermal shift assay, we confirmed AMPKα as a direct molecular target of NSC48160. Activation of AMPK was further supported by the fact that the knockdown of AMPK blocked the hepatoprotective effect of the NSC48160 and regulated its downstream pathway involved in lipogenesis by SREBP1c-FASN pathway and fatty acid oxidation by CPT1A-PPARα pathway. Moreover, NSC48160 dramatically reduces ROS production, recovers the levels of the membrane potential and NAD+/NADH, and improves the mitochondrial respiration. Conclusion and Implications: These findings suggest that NSC48160 is a promising hit compound in the pursuit of a pharmacological approach to regulate the lipogenesis and fatty acid oxidation in the treatment of nonalcoholic steatohepatitis.