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

Acta Pharmacologica Sinica volume 44, pages 2216–2229 (2023)Cite this article

Abstract

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.

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Fig. 1: 6-Methyl flavone (6-MF) inhibits the expression of Nogo-B.
Fig. 2: 6-MF ameliorates HFrD-induced metabolic disorders.
Fig. 3: 6-MF ameliorates HFrD-induced liver injury and hyperlipidemia.
Fig. 4: 6-MF decreased Nogo-B expression along with inhibiting lipid synthesis, oxidative stress, and inflammatory responses in the liver.
Fig. 5: 6-MF inhibits lipid synthesis, oxidative stress and inflammatory responses in HepG2 cells.
Fig. 6: 6-MF restores HFrD-inhibited β-oxidation and cellular autophagy.
Fig. 7: 6-MF activates HFrD-damaged autophagy via the AMPKα-mTOR pathway.

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Acknowledgements

Support was provided by China NSFC grants U22A20272 and 82173807 to YJD, 81973316 to JHH; Tianjin Municipal Science and Technology Commission of China Grant 20JCZDJC00710 and the Fundamental Research Funds for the Central Universities (Nankai University) 63211045 to JHH.

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  1. These authors contributed equally: Ke Gong, Zhen Zhang

Authors and Affiliations

  1. Key Laboratory of Metabolism and Regulation for Major Diseases of Anhui Higher Education Institutes, Hefei University of Technology, Hefei, 230031, China

    Ke Gong, Zhen Zhang, Sha-sha Chen, Xin-ran Zhu, Meng-yao Wang, Ji-hong Han & Qing-shan Li

  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

    Xin-yue Yang, Chen Ding & Ya-jun Duan

  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

    Ji-hong Han

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Contributions

KG, ZZ, QSL, JHH, and YJD designed the study, drafted and edited the manuscript; KG and ZZ performed most of the experiments; SSC, XRZ, MYW, XYY, and CD assisted with the experimental operation or data collection.

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Correspondence to Qing-shan Li or Ya-jun Duan.

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Gong, K., Zhang, Z., Chen, Ss. et al. 6-Methyl flavone inhibits Nogo-B expression and improves high fructose diet-induced liver injury in mice. Acta Pharmacol Sin 44, 2216–2229 (2023). https://doi.org/10.1038/s41401-023-01121-7

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