2. Academic Validation
  3. A novel small compound TOIDC suppresses lipogenesis via SREBP1-dependent signaling to curb MAFLD

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

  • Nutr Metab (Lond). 2022 Dec 6;19(1):80. doi: 10.1186/s12986-022-00713-0.
Yaodi Shao # 1,  Zhi Yao # 2,  Junyi Zhou 2,  Miao Yu 2,  Suzhen Chen 1,  Yanmei Yuan 1,  Liu Han 3,  Liqin Jiang 4,  Junli Liu 5
Affiliations

Affiliations

  • 1 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, Shanghai, 200233, China.
  • 2 School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China.
  • 3 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, Shanghai, 200233, China. [email protected].
  • 4 School of Chemistry and Molecular Engineering, East China Normal University, Shanghai, 200241, China. [email protected].
  • 5 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, Shanghai, 200233, China. [email protected].
  • # Contributed equally.
PMID: 36474251 DOI: 10.1186/s12986-022-00713-0
Abstract

Background: Inhibition 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.

Methods: Primary 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.

Results: We 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).

Conclusions: Our findings indicate that TOIDC could be a promising lead compound to develop new drugs to treat MAFLD.

Keywords

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

Figures
Products