Metabolic Syndrome Ameliorated by 4-Methylesculetin by Reducing Hepatic Lipid Accumulation

• Published in: International journal of molecular sciences 2022-09, Vol.23 (18), p.10465
• Main Authors: Li, Linghuan, Zhu, Guangyao, Fu, Gaohang, Zha, Weiwei, Li, Hanbing
• Format: Article
• Language: English
• Subjects: 4-methylesculetin; Accumulation; Adipocytes; adipose microenvironment; Adipose tissue; Body fat; CD36 antigen; Coumarin; Deposition; Diabetes; Energy intake; Fatty acids; Fatty liver; Fibrosis; hepatic steatosis; Hepatocytes; High fat diet; Hypertrophy; Hypoxia; Inflammation; Insulin; Insulin resistance; Lead compounds; Lipid metabolism; Lipids; Liver; Macrophages; Metabolic disorders; Metabolic syndrome; Microenvironments; Obesity; Peroxisome proliferator-activated receptors; Protein expression; Proteins; Steatosis; Sterol regulatory element-binding protein; visceral obesity
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms231810465

Obesity is a chronic metabolic disease caused by an imbalance between energy intake and expenditure during a long period and is characterized by adipose tissue disfunction and hepatic steatosis. The aim of this study was to investigate the effect of 4-methylesculetin (4-ME), a coumarin derivative, upon adipose microenvironment and hepatic steatosis in mice induced by a high-fat diet (HFD), and to explore potential mechanisms of its beneficial effect on metabolic disorders. HFD-fed mice displayed visceral obesity, insulin resistance, and hepatic lipid accumulation, which was remarkably ameliorated by 4-ME treatment. Meanwhile, 4-ME ameliorated adipocyte hypertrophy, macrophage infiltration, hypoxia, and fibrosis in epididymal adipose tissue, thus improving the adipose tissue microenvironment. Furthermore, 4-ME reversed the increase in CD36, PPAR-γ, SREBP-1, and FASN, and the decrease in CPT-1A, PPAR-α, and Nrf2 translocation into the nucleus in livers of HFD mice and in FFA-incubated hepatocytes. Moreover, the beneficial effects of 4-ME upon lipid deposition and the expression of proteins related to lipid metabolism in FFA-induced LO2 cells were abolished by ML385, a specific Nrf2 inhibitor, indicating that Nrf2 is necessary for 4-ME to reduce hepatic lipid deposition. These findings suggested that 4-ME might be a potential lead compound candidate for preventing obesity and MAFLD.