Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing
Differences in activation of mouse hepcidin by dietary iron and parenterally administered iron dextran: compartmentalization is critical for iron sensing
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DOI：
10.1007/s00109-012-0937-5
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发表时间：
2013-01-01
影响因子：
4.7
通讯作者：
Pantopoulos, Kostas
中科院分区：
文献类型：
--
作者：
Daba, Alina;Gkouvatsos, Konstantinos;Pantopoulos, Kostas
铁调节荷尔蒙海普西丁对口服和非肠道铁都有反应。在这里，我们假设不同的铁运输途径可能会影响海普西丁激活途径的动力学和动力学。为了解决这个问题，C57BL/6小鼠被给予铁强化饮食或注射。用右旋糖苷铁随时间推移进行分析。小鼠饲喂羰基铁1周后，血清铁、转铁蛋白饱和度、肝铁、Smad1/5/8磷酸化和骨形态发生蛋白6(Bmp6)及海普西丁mRNAs显著升高。然而，海普西丁的表达在之后达到了一个平台期，可能是由于抑制Smad7、Id1和Mattritase-2mRNAs的上调，而肝和脾的铁继续积累超过9周。静脉注射右旋糖酐铁后1天，小鼠的血清和肝脏铁水平升高，Smad1/5/8磷酸化，但转铁蛋白饱和度和Bmp6mRNA没有增加。令人惊讶的是，海普西丁不能对葡聚糖铁的急性超负荷做出适当的反应，并且延迟(5-7天后)海普西丁的上调与转铁蛋白饱和度的增加、铁从巨噬细胞到肝细胞的部分重新定位以及Bmp6mRNA的诱导有关。我们的数据表明，海普西丁的生理反应是可饱和的，并与海普西丁只感知循环转铁蛋白和/或肝细胞内的铁区隔的想法一致。
The iron regulatory hormone hepcidin responds to both oral and parenteral iron. Here, we hypothesized that the diverse iron trafficking routes may affect the dynamics and kinetics of the hepcidin activation pathway. To address this, C57BL/6 mice were administered an iron-enriched diet or injected i.p. with iron dextran and analyzed over time. After 1 week of dietary loading with carbonyl iron, mice exhibited significant increases in serum iron and transferrin saturation, as well as in hepatic iron, Smad1/5/8 phosphorylation and bone morphogenetic protein 6 (BMP6), and hepcidin mRNAs. Nevertheless, hepcidin expression reached a plateau afterward, possibly due to upregulation of inhibitory Smad7, Id1, and matriptase-2 mRNAs, while hepatic and splenic iron continued to accumulate over 9 weeks. One day following parenteral administration of iron dextran, mice manifested elevated serum and hepatic iron levels and Smad1/5/8 phosphorylation, but no increases in transferrin saturation or BMP6 mRNA. Surprisingly, hepcidin failed to appropriately respond to acute overload with iron dextran, and a delayed (after 5-7 days) hepcidin upregulation correlated with increased transferrin saturation, partial relocation of iron from macrophages to hepatocytes, and induction of BMP6 mRNA. Our data suggest that the physiological hepcidin response is saturable and are consistent with the idea that hepcidin senses exclusively iron compartmentalized within circulating transferrin and/or hepatocytes.