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

作　　者：Ke Gong Zhen Zhang Sha-sha Chen Xin-ran Zhu Meng-yao Wang Xin-yue Yang Chen Ding Ji-hong Han Qing-shan Li Ya-jun Duan 

机构地区：[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

出　　处：《Acta Pharmacologica Sinica》2023年第11期2216-2229,共14页中国药理学报（英文版）

基　　金：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.

摘　　要：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.

关 键 词：metabolic syndrome glycolipid metabolism liver injury high fructose 6-methyl flavone Nogo-B 

分 类 号：R285.5[医药卫生—中药学]