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 

作者机构：Clinical Medicine Research Institute and Department of Metabolic and Bariatric Surgerythe First Affiliated Hospital of Jinan UniversityGuangzhou 510632China Department of Obstetricsthe Third Affiliated HospitalSun Yat-sen UniversityGuangzhou 510630China Faculty of Pharmaceutical SciencesToho UniversityChiba 2748510Japan Department of General Surgeryand Institute of Hepato-Biliary-Pancreas and Intestinal DiseaseAffiliated Hospital of North Sichuan Medical CollegeNanchong 637000China GMH Institute of CNS RegenerationGuangdong Medical Key Laboratory of Brain Function and DiseasesJinan UniversityGuangzhou 510632China School of Biomedical SciencesLKS Faculty of Medicinethe University of Hong KongHong KongChina Division of GastroenterologySeventh Affiliated Hospital of Sun Yat-sen UniversityShenzhen 518107China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2023年第13卷第1期

页      面：100-112页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1002[医学-临床医学] 10[医学] 

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)。 

主　　题：Alcoholic liver disease Melatonin Binding receptor TERT EGFR BRG1 Biophysics Safety 

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.