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

Ke Gong1, Zhen Zhang1, Sha-sha Chen1, Xin-ran Zhu1, Meng-yao Wang1, Xin-yue Yang2, Chen Ding2, Ji-hong Han1,3, Qing-shan Li1, Ya-jun Duan2
1 Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei 230031, China
2 Department of Cardiology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230001, China
3 College of Life Sciences, State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin 300071, China
Correspondence to: Qing-shan Li:, Ya-jun Duan:,
DOI: 10.1038/s41401-023-01121-7
Received: 2 March 2023
Accepted: 1 June 2023
Advance online: 4 July 2023


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 μM. 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 μM) 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 AMPKα-mTOR pathway. Thus, 6-MF may serve as a potential Nogo-B inhibitor to treat metabolic syndrome caused by glycolipid metabolism dysregulation.

Keywords: metabolic syndrome; glycolipid metabolism; liver injury; high fructose; 6-methyl flavone; Nogo-B

Article Options

Download Citation

Cited times in Scopus