title: The dietary flavonoid myricetin regulates iron homeostasis by suppressing hepcidin expression.
abstract: Hepcidin, a master regulator of iron homeostasis, is a promising target in treatment of iron disorders such as hemochromatosis, anemia of inflammation and iron-deficiency anemia. We previously reported that black soybean seed coat extract could inhibit hepcidin expression. Based on this finding, we performed a screen in cultured cells in order to identify the compounds in black soybeans that inhibit hepcidin expression. We found that the dietary flavonoid myricetin significantly inhibited the expression of hepcidin both in vitro and in vivo. Treating cultured cells with myricetin decreased both HAMP mRNA levels and promoter activity by reducing SMAD1/5/8 phosphorylation. This effect was observed even in the presence of bone morphogenic protein-6 (BMP6) and interleukin-6 (IL-6), two factors that stimulate hepcidin expression. Furthermore, mice that were treated with myricetin (either orally or systemically) had reduced hepatic hepcidin expression, decreased splenic iron levels and increased serum iron levels. Notably, myricetin-treated mice increased red blood cell counts and hemoglobin levels. In addition, pretreating mice with myricetin prevented LPS-induced hypoferremia. We conclude that myricetin potently inhibits hepcidin expression both in vitro and in vivo, and this effect is mediated by altering BMP/SMAD signaling. These experiments highlight the feasibility of identifying and characterizing bioactive phytochemicals to suppress hepcidin expression. These results also suggest that myricetin may represent a novel therapy for treating iron deficiency-related diseases.
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Institute, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Mingdao
authors.initials: M
authors.lastname: Mu
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China; The first affiliated Hospital, Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Peng
authors.initials: P
authors.lastname: An
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Wu
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Shen
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Dandan
authors.initials: D
authors.lastname: Shao
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China.
authors.forename: Yingqi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Institute, College of Public Health, Zhengzhou University, Zhengzhou 450001, China.
authors.forename: Shenshen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Traditional Chinese Medicine Department, Zhejiang Hospital, Hangzhou 310013, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Yao
authors.affiliation: The first affiliated Hospital, Institute for Translational Medicine, School of Medicine, Zhejiang University, Hangzhou 310058, China.
authors.forename: Junxia
authors.initials: J
authors.lastname: Min
authors.affiliation: Department of Nutrition, Nutrition Discovery Innovation Institute, College of Public Health, Zhengzhou University, Zhengzhou 450001, China; Department of Nutrition, Nutrition Discovery Innovation Center, Institute of Nutrition and Food Safety, School of Public Health, School of Medicine, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang 310058, China. Electronic address: fudiwang.lab@gmail.com.
authors.forename: Fudi
authors.initials: F
authors.lastname: Wang
mesh_terms: D000818:Animals; D005419:Flavonoids / Q000494:pharmacology*; D064451:Hepcidins / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects*; D007501:Iron / Q000378:metabolism*; D051379:Mice
chemical_list: D005419:Flavonoids; D064451:Hepcidins; C040015:myricetin; D007501:Iron
keywords: Anemia of inflammation; Hepcidin; Iron metabolism; Iron-deficiency anemia; Myricetin