Institute of Veterinary Physiology, Vetsuisse Faculty, and Zurich Center for Integrative Human Physiology (ZIHP), and University of Zurich, Switzerland; Department of Health and Human Performance, Faculty of Sports Science, INEF, Technical University of Madrid, Spain.
Hepatology. 2013 Dec;58(6):2122-32. doi: 10.1002/hep.26550. Epub 2013 Oct 21.
The liver-derived peptide hepcidin controls the balance between iron demand and iron supply. By inhibiting the iron export activity of ferroportin, hepcidin modulates iron absorption and delivery from the body's stores. The regulation of hepcidin, however, is not completely understood and includes a variety of different signals. We studied iron metabolism and hepcidin expression in mice constitutively overexpressing erythropoietin (Epo) (Tg6 mice), which leads to excessive erythropoiesis. We observed a very strong down-regulation of hepcidin in Tg6 mice that was accompanied by a strong increase in duodenal expression of ferroportin and divalent metal tranporter-1, as well as enhanced duodenal iron absorption. Despite these compensatory mechanisms, Tg6 mice displayed marked circulating iron deficiency and low levels of iron in liver, spleen, and muscle. To elucidate the primary signal affecting hepcidin expression during chronically elevated erythropoiesis, we increased iron availability by either providing iron (thus further increasing the hematocrit) or reducing erythropoiesis-dependent iron consumption by means of splenectomy. Both treatments increased liver iron and up-regulated hepcidin expression and the BMP6/SMAD pathway despite continuously high plasma Epo levels and sustained erythropoiesis. This suggests that hepcidin expression is not controlled by erythropoietic signals directly in this setting. Rather, these results indicate that iron consumption for erythropoiesis modulates liver iron content, and ultimately BMP6 and hepcidin. Analysis of the BMP6/SMAD pathway targets showed that inhibitor of DNA binding 1 (ID1) and SMAD7, but not transmembrane serine protease 6 (TMPRSS6), were up-regulated by increased iron availability and thus may be involved in setting the upper limit of hepcidin.
We provide evidence that under conditions of excessive and effective erythropoiesis, liver iron regulates hepcidin expression through the BMP6/SMAD pathway.
肝脏来源的肽hepcidin 控制铁需求和铁供应之间的平衡。hepcidin 通过抑制铁输出活性的 ferroportin，调节铁吸收和从身体储存中释放。然而，hepcidin 的调节并不完全清楚，包括各种不同的信号。我们研究了在红细胞生成素（Epo）（Tg6 小鼠）持续过表达的小鼠中铁代谢和 hepcidin 表达，这导致了过度的红细胞生成。我们观察到 Tg6 小鼠中 hepcidin 的下调非常强烈，同时十二指肠中 ferroportin 和二价金属转运蛋白-1 的表达增加，以及十二指肠铁吸收增强。尽管存在这些代偿机制，Tg6 小鼠仍表现出明显的循环铁缺乏和肝、脾、肌肉中铁含量低。为了阐明在慢性升高的红细胞生成过程中影响 hepcidin 表达的主要信号，我们通过提供铁（从而进一步增加红细胞压积）或通过脾切除术减少红细胞生成依赖性铁消耗来增加铁的可用性。这两种治疗方法都增加了肝脏铁含量，并上调了 hepcidin 表达和 BMP6/SMAD 通路，尽管持续高血浆 Epo 水平和持续的红细胞生成。这表明在这种情况下，hepcidin 表达不受红细胞生成信号的直接控制。相反，这些结果表明，用于红细胞生成的铁消耗调节肝脏铁含量，并最终调节 BMP6 和 hepcidin。BMP6/SMAD 通路靶标分析表明，DNA 结合抑制因子 1（ID1）和 SMAD7，但不是跨膜丝氨酸蛋白酶 6（TMPRSS6），被增加的铁可用性上调，因此可能参与设定 hepcidin 的上限。
我们提供的证据表明，在过度和有效的红细胞生成条件下，肝脏铁通过 BMP6/SMAD 通路调节 hepcidin 表达。
