Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.
Evidence for distinct pathways of hepcidin regulation by acute and chronic iron loading in mice.
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通过小鼠急性和慢性铁负荷调节肝素调节的不同途径的证据。
DOI：
10.1002/hep.24178
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发表时间：
2011-04
期刊：
影响因子：
13.5
通讯作者：
Ganz, Tomas
中科院分区：
文献类型：
--
作者：
Ramos, Emilio;Kautz, Leon;Rodriguez, Richard;Hansen, Michael;Gabayan, Victoria;Ginzburg, Yelena;Roth, Marie-Paule;Nemeth, Elizabeta;Ganz, Tomas
铁调素合成对铁负荷的反应是稳态增加，以限制膳食铁的进一步吸收及其从储存中释放。HFE、转铁蛋白受体2（Tfr 2）、血幼素（HJV）或骨形态发生蛋白6（BMP 6）中的突变阻止铁调素对铁的适当反应，从而增加膳食铁的吸收，并最终导致铁过载。为了了解这些蛋白质中的每一个在铁调素调节铁中所起的作用，我们分析了铁调素mRNA对铁缺乏的Hfe，Tfr 2，Hisp和Bmp 6突变小鼠的短期和长期铁挑战的反应。在1天（急性）铁挑战后，Hfe−/−表现出比野生型菌株匹配对照更小的hepcidin增加，Bmp 6 −/−几乎没有增加，Tfr 2和Hepcidin突变体没有增加hepcidin表达，表明所有四种蛋白质都参与了铁调素的急性铁变化调节。在21天（慢性）铁挑战后，Hfe和Tfr 2突变体将hepcidin表达增加到接近野生型水平，但在Bmp 6 −/−和Hps 6 −/−小鼠中观察到hepcidin的钝性增加。BMP 6的表达也受铁的调节，可能通过铁储存介导铁调素的调节。没有突变株（Bmp 6 −/−小鼠除外）对慢性铁负荷的BMP 6 mRNA反应受损。结论：TfR 2、HJV和BMP 6以及在较小程度上HFE是铁调素对急性铁负荷的响应所需的，但在慢性铁负荷期间对于铁调素调节是部分冗余的，并且不参与BMP 6表达的调节。我们的研究结果支持一种模型，其中通过HFE，TfR 2和HJV传输的全转铁蛋白浓度的急性增加增加BMP受体对BMP的敏感性。一个独特的调节机制，感觉肝脏铁可能会调节铁调素对慢性铁负荷的反应。
In response to iron loading, hepcidin synthesis is homeostatically increased to limit further absorption of dietary iron and its release from stores. Mutations in HFE, transferrin receptor 2 (Tfr2), hemojuvelin (HJV) or bone morphogenetic protein 6 (BMP6) prevent appropriate hepcidin response to iron, allowing increased absorption of dietary iron, and eventually iron overload. To understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin mRNA responsiveness to short and long-term iron challenge in iron-depleted Hfe, Tfr2, Hjv and Bmp6 mutant mice. After 1-day (acute) iron challenge, Hfe−/− showed a smaller hepcidin increase than their wild-type strain-matched controls, Bmp6−/− nearly no increase, and Tfr2 and Hjv mutants no increase in hepcidin expression, indicating that all four proteins participate in hepcidin regulation by acute iron changes. After a 21-day (chronic) iron challenge, Hfe and Tfr2 mutants increased hepcidin expression to nearly wild-type levels but a blunted increase of hepcidin was seen in Bmp6−/− and Hjv−/− mice. BMP6, whose expression is also regulated by iron, may mediate hepcidin regulation by iron stores. None of the mutant strains (excepting Bmp6−/− mice) had impaired BMP6 mRNA response to chronic iron loading. Conclusion: TfR2, HJV and BMP6 and, to a lesser extent, HFE, are required for the hepcidin response to acute iron loading, but are partially redundant for hepcidin regulation during chronic iron loading, and are not involved in the regulation of BMP6 expression. Our findings support a model in which acute increases in holotransferrin concentrations transmitted through HFE, TfR2 and HJV augment BMP receptor sensitivity to BMPs. A distinct regulatory mechanism that senses hepatic iron may modulate hepcidin response to chronic iron loading.
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影响因子：
10.1
作者：
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通讯作者：
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