Quercetin prevents ethanol-induced iron overload by regulating hepcidin through the BMP6/SMAD4 signaling pathway |
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| Affiliation: | 1. 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;2. Department of Infectious Diseases, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China;1. Vascular Medicine and Metabolism Unit and Research Unit on Lipids and Atherosclerosis, Sant Joan University Hospital, IISPV, Rovira i Virgili University, 43201 Reus, Spain;2. Spanish Biomedical Research Network in Diabetes and Associated Metabolic Disorders (CIBERDEM), 08017 Barcelona, Spain;3. Lipid Clinic, Endocrinology and Nutrition Service, Biomedical Research Institute August Pi i Sunyer (IDIBAPS), Hospital Clínic, 08036 Barcelona, Spain;4. CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain;5. Cardiometabolic Research Institute, 7505 Fannin Street Suite 210, Houston, TX 77054, USA;1. Laboratory of Fruit Quality Biology, Zhejiang University, Zijingang Campus, Hangzhou 310058, China;2. The State Agriculture Ministry Laboratory of Horticultural Plant Growth, Zhejiang University, Zijingang Campus, Hangzhou 310058, China;3. Zhejiang Key Laboratory for Agro-Food Processing, Development and Quality Improvement, Zhejiang University, Zijingang Campus, Hangzhou 310058, China |
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| 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. |
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