6-Methyl flavone inhibits Nogo-B expression and improves high fructose diet-induced liver injury in mice

作者：Gong, Ke; Zhang, Zhen; Chen, Sha-sha; Zhu, Xin-ran; Wang, Meng-yao; Yang, Xin-yue; Ding, Chen; Han, Ji-hong; Li, Qing-shan^*; Duan, Ya-jun^*

来源：Acta Pharmacologica Sinica, 2023, 44(11): 2216-2229.

DOI：10.1038/s41401-023-01121-7

• metabolic syndrome
• glycolipid metabolism
• liver injury
• high fructose
• 6-methyl flavone
• Nogo-B

Excessive fructose consumption increases hepatic de novo lipogenesis, resulting in cellular stress, inflammation and liver injury. Nogo-B is a resident protein of the endoplasmic reticulum that regulates its structure and function. Hepatic Nogo-B is a key protein in glycolipid metabolism, and inhibition of Nogo-B has protective effects against metabolic syndrome, thus small molecules that inhibit Nogo-B have therapeutic benefits for glycolipid metabolism disorders. In this study we tested 14 flavones/isoflavones in hepatocytes using dual luciferase reporter system based on the Nogo-B transcriptional response system, and found that 6-methyl flavone (6-MF) exerted the strongest inhibition on Nogo-B expression in hepatocytes with an IC50 value of 15.85 mu M. Administration of 6-MF (50 mg.kg(-1).d(-1), i.g. for 3 weeks) significantly improved insulin resistance along with ameliorated liver injury and hypertriglyceridemia in high fructose diet-fed mice. In HepG2 cells cultured in a media containing an FA-fructose mixture, 6-MF (15 mu M) significantly inhibited lipid synthesis, oxidative stress and inflammatory responses. Furthermore, we revealed that 6-MF inhibited Nogo-B/ChREBP-mediated fatty acid synthesis and reduced lipid accumulation in hepatocytes by restoring cellular autophagy and promoting fatty acid oxidation via the AMPKa-mTOR pathway. Thus, 6-MF may serve as a potential Nogo-B inhibitor to treat metabolic syndrome caused by glycolipid metabolism dysregulation.

• 单位
  1; 南开大学