The dietary flavonoid myricetin regulates iron homeostasis by suppressing hepcidin expression
The dietary flavonoid myricetin regulates iron homeostasis by suppressing hepcidin expression
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膳食类黄酮杨梅素通过抑制铁调素表达来调节铁稳态
DOI：
10.1016/j.jnutbio.2015.10.015
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发表时间：
2016-04-01
影响因子：
5.6
通讯作者：
Wang, Fudi
中科院分区：
文献类型：
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作者：
Mu, Mingdao;An, Peng;Wang, Fudi
铁调素是铁稳态的主要调节剂，是治疗血色素沉着症、炎症性贫血和缺铁性贫血等铁代谢疾病的一个很有前途的靶点。我们以前报道过黑大豆种皮提取物可以抑制hepcidin的表达。基于这一发现，我们在培养的细胞中进行了筛选，以鉴定黑豆中抑制hepcidin表达的化合物。我们发现，膳食黄酮杨梅素显着抑制hepcidin在体外和体内的表达。用杨梅素处理培养的细胞通过减少SMAD 1/5/8磷酸化而降低HAMP mRNA水平和启动子活性。即使在骨形态发生蛋白-6（BMP-6）和白细胞介素-6（IL-6）（两种刺激铁调素表达的因子）存在下也观察到这种效应。此外，用杨梅素（口服或全身）治疗的小鼠具有降低的肝铁调素表达、降低的脾铁水平和增加的血清铁水平。值得注意的是，杨梅素处理的小鼠增加了红细胞计数和血红蛋白水平。此外，用杨梅素预处理小鼠可预防LPS诱导的低铁血症。我们的结论是，杨梅素有效地抑制hepcidin表达在体外和体内，这种效果是通过改变BMP/SMAD信号介导的。这些实验突出了鉴定和表征生物活性植物化学物质以抑制铁调素表达的可行性。这些结果也表明，杨梅素可能是一种新的治疗缺铁相关疾病的疗法。(C)2015爱思唯尔公司All rights reserved.
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. (C) 2015 Elsevier Inc. All rights reserved.