Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation  

作　　者：Zhaodi Che Yali Song Chengfang Xu Wei Li Zhiyong Dong Cunchuan Wang Yixing Ren Kwok-Fai So George L.Tipoe Fei Wang Jia Xiao 

机构地区：[1]Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgery,the First Affiliated Hospital of Jinan University,Guangzhou 510632,China [2]Department of Obstetrics,the Third Affiliated Hospital,Sun Yat-sen University,Guangzhou 510630,China [3]Faculty of Pharmaceutical Sciences,Toho University,Chiba 2748510,Japan [4]Department of General Surgery,and Institute of Hepato-Biliary-Pancreas and Intestinal Disease,Affiliated Hospital of North Sichuan Medical College,Nanchong 637000,China [5]GMH Institute of CNS Regeneration,Guangdong Medical Key Laboratory of Brain Function and Diseases,Jinan University,Guangzhou 510632,China [6]School of Biomedical Sciences,LKS Faculty of Medicine,the University of Hong Kong,Hong Kong,China [7]Division of Gastroenterology,Seventh Affiliated Hospital of Sun Yat-sen University,Shenzhen 518107,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第1期100-112,共13页药学学报（英文版）

基　　金：supported by grants from National Natural Science Foundation of China(82122009,82170605,81873573 and 81970515);Guangdong Natural Science Funds for Distinguished Young Scholar(2019B151502013,China)。

摘　　要：Chronic alcohol consumption causes liver steatosis,cell death,and inflammation.Melatonin(MLT)is reported to alleviate alcoholic liver disease(ALD)-induced injury.However,its direct regulating targets in hepatocytes are not fully understood.In the current study,a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT.MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models(optimal doses of 10μmol/L and 5 mg/kg,respectively),including lowered liver steatosis,cell death,and inflammation.RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase(TERT)was a key downstream effector of MLT.Biophysical assay found that epidermal growth factor receptor(EGFR)on the hepatocyte surface was a direct binding and regulating target of MLT.Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection,partly through the regulation of nuclear brahma-related gene-1(BRG1).Long-term administration(90 days)of MLT in healthy mice did not cause evident adverse effect.In conclusion,MLT is an efficacious and safe agent for ALD alleviation.Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis.MLT might be used as a complimentary agent for alcoholics.

关 键 词：Alcoholic liver disease MELATONIN Binding receptor TERT EGFR BRG1 BIOPHYSICS Safety 

分 类 号：R575[医药卫生—消化系统]