Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe.
Iron regulation of hepcidin despite attenuated Smad1,5,8 signaling in mice without transferrin receptor 2 or Hfe.
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尽管没有转铁蛋白受体2或HFE的小鼠，但肝素的铁调节仍减弱了1,5,8的信号传导。
DOI：
10.1053/j.gastro.2011.06.077
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发表时间：
2011-11
期刊：
影响因子：
29.4
通讯作者：
Fleming RE
中科院分区：
文献类型：
--
作者：
Corradini E;Rozier M;Meynard D;Odhiambo A;Lin HY;Feng Q;Migas MC;Britton RS;Babitt JL;Fleming RE
HFE和转铁蛋白受体2(TFR2)对于体内铁状态和肝脏海普西丁表达之间的正常关系都是必需的。在遗传性血色沉着症(HH)的小鼠HFE和Tfr2基因敲除模型中，通过骨形态发生蛋白6(Bmp6)/Smad1，5，8途径向海普西丁的信号转导减弱。我们利用靶向干扰Tfr2、HFe或两者的小鼠，研究了膳食铁对通过Bmp6/Smad1、5、8途径调节海普西丁表达的影响。在标准或铁负荷饮食的HH模型中，将每种HH模型中的肝脏铁浓度以及Bmp6和海普西丁的mRNA表达与野生型小鼠进行比较。检测肝组织磷酸化Smad(P-Smad)1、5、8和Id1mRNA水平，作为BMP/Smad信号转导的标志物。与野生型小鼠相比，各HH模型小鼠肝组织中Bmp6的表达增加，而肝组织中的海普西丁和Id1的表达降低。每个HH模型还显示出与肝铁状态相关的P-Smad1、5、8水平降低。HFe/Tfr2联合干扰的小鼠受影响最大。在每种HH模型中，膳食铁负荷增加了海普西丁和Id1的表达。与野生型小鼠相比，HH小鼠表现出对膳食铁负荷的P-Smad1，5，8水平的减弱(HFe基因敲除)或不增加。这些观察结果表明，Tfr2和HFe都是通过Bmp6/Smad1，5，8途径向海普西丁发出正常的铁状态信号所必需的。HFe和Tfr2共同缺失的小鼠在饮食铁负荷下上调了海普西丁的表达，而肝脏Bmp6mRNA或稳态P-Smad1、5、8水平没有增加。
HFE and transferrin receptor 2 (TFR2) are each necessary for the normal relationship between body iron status and liver hepcidin expression. In murine Hfe and Tfr2 knockout models of hereditary hemochromatosis (HH), signal transduction to hepcidin via the bone morphogenetic protein 6 (Bmp6)/Smad1,5,8 pathway is attenuated. We examined the effect of dietary iron on regulation of hepcidin expression via the Bmp6/Smad1,5,8 pathway using mice with targeted disruption of Tfr2, Hfe, or both genes. Hepatic iron concentrations and mRNA expression of Bmp6 and hepcidin were compared with wild-type mice in each of the HH models on standard or iron-loading diets. Liver phospho-Smad (P-Smad)1,5,8 and Id1 mRNA levels were measured as markers of Bmp/Smad signaling. While Bmp6 expression was increased, liver hepcidin and Id1 expression were decreased in each of the HH models compared with wild-type mice. Each of the HH models also demonstrated attenuated P-Smad1,5,8 levels relative to liver iron status. Mice with combined Hfe/Tfr2 disruption were most affected. Dietary iron loading increased hepcidin and Id1 expression in each of the HH models. Compared with wild-type mice, HH mice demonstrated attenuated (Hfe knockout) or no increases in P-Smad1,5,8 levels in response to dietary iron loading. These observations demonstrate that Tfr2 and Hfe are each required for normal signaling of iron status to hepcidin via Bmp6/Smad1,5,8 pathway. Mice with combined loss of Hfe and Tfr2 up-regulate hepcidin in response to dietary iron loading without increases in liver BMP6 mRNA or steady-state P-Smad1,5,8 levels.
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影响因子：
168.9
作者：
Bridle, KR;Frazer, DM;Ramm, GA
通讯作者：
Ramm, GA
影响因子：
15.9
作者：
Babitt, Jodie L.;Huang, Franklin W.;Lin, Herbert Y.
通讯作者：
Lin, Herbert Y.
影响因子：
4.8
作者：
Goswami, Tapasree;Andrews, Nancy C.
通讯作者：
Andrews, Nancy C.
影响因子：
2.3
作者：
Bolondi, Giuliano;Garuti, Cinzia;Corradini, Elena;Zoller, Heinz;Vogel, Wolfgang;Finkenstedt, Armin;Babitt, Jodie L.;Lin, Herbert Y.;Pietrangelo, Antonello
通讯作者：
Pietrangelo, Antonello
影响因子：
20.3
作者：
Kawabata, H;Fleming, RE;Koeffler, HP
通讯作者：
Koeffler, HP