title: Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway.
abstract: Emerging evidence has demonstrated that chronic ethanol exposure induces iron overload, enhancing ethanol-mediated liver damage. The purpose of this study was to explore the effects of the naturally occurring compound quercetin on ethanol-induced iron overload and liver damage, focusing on the signaling pathway of the iron regulatory hormone hepcidin. Adult male C57BL/6J mice were pair-fed with isocaloric-Lieber De Carli diets containing ethanol (accounting for 30% of total calories) and/or carbonyl iron (0.2%) and treated with quecertin (100 mg/kg body weight) for 15 weeks. Mouse primary hepatocytes were incubated with ethanol (100 mM) and quercetin (100 μM) for 24 h. Mice exposed to either ethanol or iron presented significant fatty infiltration and iron deposition in the liver; these symptoms were exacerbated in mice cotreated with ethanol and iron. Quercetin attenuated the abnormity induced by ethanol and/or iron. Ethanol suppressed BMP6 and intranuclear SMAD4 as well as decreased hepcidin expression. These effects were partially alleviated by quercetin supplementation in mice and hepatocytes. Importantly, ethanol caused suppression of SMAD4 binding to the HAMP promoter and of hepcidin messenger RNA expression. These effects were exacerbated by anti-BMP6 antibody and partially alleviated by quercetin or human recombinant BMP6 in cultured hepatocytes. In contrast, co-treatment with iron and ethanol, especially exposure of iron alone, activated BMP6/SMAD4 pathway and up-regulated hepcidin expression, which was also normalized by quercetin in vivo. Quercetin prevented ethanol-induced hepatic iron overload different from what carbonyl iron diet elicited in the mechanism, by regulating hepcidin expression via the BMP6/SMAD4 signaling pathway.
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yuhan
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Yanyan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Gao
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Shaodan
authors.initials: S
authors.lastname: Chen
authors.affiliation: Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Mingyou
authors.initials: M
authors.lastname: Xing
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
authors.forename: Liegang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, Ministry of Education Key Laboratory of Environment and Health and MOE Key Lab of Environment and Health, Key Laboratory of Environment and Health (Wuhan), Ministry of Environmental Protection, State Key Laboratory of Environment Health (Incubation), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Electronic address: yaoping@mails.tjmu.edu.cn.
authors.forename: Ping
authors.initials: P
authors.lastname: Yao
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000627:therapeutic use*; D055418:Bone Morphogenetic Protein 6 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D019587:Dietary Supplements; D004195:Disease Models, Animal; D000431:Ethanol; D005786:Gene Expression Regulation; D048550:Hepatic Insufficiency / Q000209:etiology / Q000517:prevention & control*; D022781:Hepatocytes / Q000378:metabolism; D064451:Hepcidins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D054354:Iron Carbonyl Compounds; D019190:Iron Overload / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D011794:Quercetin / Q000378:metabolism / Q000627:therapeutic use*; D011897:Random Allocation; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D051901:Smad4 Protein / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D000975:Antioxidants; D055418:Bone Morphogenetic Protein 6; D064451:Hepcidins; D011994:Recombinant Proteins; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D054354:Iron Carbonyl Compounds; D000431:Ethanol; D011794:Quercetin
keywords: Alcoholic liver diseases (ALD); Bone morphogenetic protein 6 (BMP6)/ SMAD4; Hepcidin; Iron overload; Quercetin