title: Glycycoumarin ameliorates alcohol-induced hepatotoxicity via activation of Nrf2 and autophagy.
abstract: Licorice, a traditional Chinese medicine, has been used to treat various diseases, including liver disease, for centuries. However, the chemical basis and biological mechanisms underlying the biological functions of licorice remain elusive. The purpose of the current study was to test the hepatoprotective effect of glycycoumarin (GCM), a representative coumarin in licorice, using animal models of both chronic and acute alcoholic liver injury. C57BL/6J mice were used to evaluate the hepatoprotective effect of GCM on liver injury induced by either chronic or acute ethanol exposure. AML-12 and HepG2 cells were utilized to determine the functional role of Nrf2 in the hepatoprotective effect of GCM and to decipher the mechanisms of GCM-induced Nrf2 activation. We found that treatment with GCM leads to a significant reduction in hepatotoxicity in response to either chronic or acute ethanol exposure. Further mechanistic investigations reveal that activation of Nrf2 via the p38 pathway and induction of autophagy by GCM contribute to its hepatoprotective activity. In addition, we demonstrate that p62 upregulation by a transcriptional mechanism also contributes to Nrf2 activation via a positive feedback loop. Our study has identified GCM as a novel active ingredient that contributes to the hepatoprotective activity of licorice.
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Xinhua
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Shutao
authors.initials: S
authors.lastname: Yin
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Yazhen
authors.initials: Y
authors.lastname: Huo
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China.
authors.forename: Min
authors.initials: M
authors.lastname: Liang
authors.affiliation: College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
authors.forename: Lihong
authors.initials: L
authors.lastname: Fan
authors.affiliation: State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China. Electronic address: yemin@bjmu.edu.cn.
authors.forename: Min
authors.initials: M
authors.lastname: Ye
authors.affiliation: Department of Nutrition and Health, College of Food Science and Nutritional Engineering, China Agricultural University, Beijing 100083, China. Electronic address: hongbo@cau.edu.cn.
authors.forename: Hongbo
authors.initials: H
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002492:Central Nervous System Depressants / Q000633:toxicity; D003374:Coumarins / Q000494:pharmacology*; D000431:Ethanol / Q000633:toxicity*; D005455:Fluorescent Antibody Technique; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D002492:Central Nervous System Depressants; D003374:Coumarins; D051267:NF-E2-Related Factor 2; D012333:RNA, Messenger; C515155:glycycoumarin; D000431:Ethanol
keywords: Alcoholic liver injury; Autophagy; Free radicals; Glycycoumarin; Licorice; Nrf2