A novel small compound TOIDC suppresses lipogenesis via SREBP1-dependent signaling to curb MAFLD

Nutrition & Metabolism

Research

Junyi Zhou¹  Miao Yu¹  Liqin Jiang¹  Zhi Yao¹  Yanmei Yuan²  Suzhen Chen²  Liu Han²  Junli Liu²  Yaodi Shao² 

[1] School of Chemistry and Molecular Engineering, East China Normal University, 200241, Shanghai, China;Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 200233, Shanghai, China;

关键词: Metabolic-associated fatty liver disease;    High content screening;    Pharmacotherapy;    Sterol regulatory element-binding protein 1;    De novo lipogenesis;   

DOI  :  10.1186/s12986-022-00713-0

 received in 2022-10-11, accepted in 2022-11-12,  发布年份 2022

来源: Springer

【 摘 要 】

BackgroundInhibition of hepatic lipogenesis is widely regarded as an effective treatment for metabolic-associated fatty liver disease (MAFLD), although numerous related drugs have failed to reach clinical application. The goal of this study is to identify a novel small compound that can effectively treat MAFLD.MethodsPrimary hepatocytes were first exposed to palmitic acid and oleic acid, then treated with compounds prior to high through screening for cellular lipid content. The efficacy of these compounds was measured by Nile Red staining and triglyceride analysis. The potential cellular toxicity caused by these compounds was evaluated by CCK8 assay. qPCR and Western blot were used to determine expression of RNAs and proteins, respectively. The compound was intraperitoneally injected into diet-induced obese (DIO) mice to examine its efficacy in vivo.ResultsWe identified the dimethyl 1-methyl-2-thioxoindoline-3,3-dicarboxylate (TOIDC) as a powerful chemical to reduce cellular lipid with minimal cellular toxicity. When injected intraperitoneally, TOIDC effectively ameliorates MAFLD in DIO mice. Mechanically, TOIDC suppresses de novo lipogenesis through inhibiting sterol regulatory element-binding protein 1 (SREBP1).ConclusionsOur findings indicate that TOIDC could be a promising lead compound to develop new drugs to treat MAFLD.Graphical Abstract

【 授权许可】

CC BY   
© The Author(s) 2022

【 图 表 】

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