Zhang Zhuzhen, Guo Xin, Herrera Carolina, Tao Yunlong, Wu Qian, Wu Aimin, Wang Hao, Bartnikas Thomas B, Wang Fudi
Laboratory of Nutrition and Metabolism, Center for Nutrition and Health, Department of Nutrition, Institute of Nutrition and Food Safety, School of Public Health, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, Zhejiang, China ; Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai, China.
Department of Pathology and Laboratory Medicine, Brown University, Providence, Rhode Island, United States of America.
PLoS One. 2014 Jan 13;9(1):e84906. doi: 10.1371/journal.pone.0084906. eCollection 2014.
The liver is the primary organ for storing iron and plays a central role in the regulation of body iron levels by secretion of the hormone Hamp1. Although many factors modulate Hamp1 expression, their regulatory mechanisms are poorly understood. Here, we used conditional knockout mice for the iron exporter ferroportin1 (Fpn1) to modulate tissue iron in specific tissues in combination with iron-deficient or iron-rich diets and transferrin (Tf) supplementation to investigate the mechanisms underlying Hamp1 expression. Despite liver iron overload, expression of bone morphogenetic protein 6 (Bmp6), a potent-stimulator of Hamp1 expression that is expressed under iron-loaded conditions, was decreased. We hypothesized that factors other than liver iron must play a role in controlling Bmp6 expression. Our results show that erythropoietin and Tf-bound iron do not underlie the down-regulation of Bmp6 in our mice models. Moreover, Bmp6 was down-regulated under conditions of high iron demand, irrespective of the presence of anemia. We therefore inferred that the signals were driven by high iron demand. Furthermore, we also confirmed previous suggestions that Tf-bound iron regulates Hamp1 expression via Smad1/5/8 phosphorylation without affecting Bmp6 expression, and the effect of Tf-bound iron on Hamp1 regulation appeared before a significant change in Bmp6 expression. Together, these results are consistent with novel mechanisms for regulating Bmp6 and Hamp1 expression.
肝脏是储存铁的主要器官，通过分泌激素Hamp1在调节机体铁水平方面发挥核心作用。尽管有许多因素调节Hamp1的表达，但其调控机制仍知之甚少。在此，我们使用铁输出蛋白铁转运蛋白1（Fpn1）的条件性敲除小鼠，结合缺铁或富铁饮食以及转铁蛋白（Tf）补充剂来调节特定组织中的组织铁，以研究Hamp1表达的潜在机制。尽管肝脏铁过载，但在铁负荷条件下表达的Hamp1表达的强效刺激因子骨形态发生蛋白6（Bmp6）的表达却降低了。我们推测除肝脏铁之外的其他因素必定在控制Bmp6表达中发挥作用。我们的结果表明，促红细胞生成素和与Tf结合的铁并非我们小鼠模型中Bmp6下调的原因。此外，在高铁需求条件下，无论是否存在贫血，Bmp6都会下调。因此我们推断这些信号是由高铁需求驱动的。此外，我们还证实了先前的观点，即与Tf结合的铁通过Smad1/5/8磷酸化调节Hamp1表达而不影响Bmp6表达，并且与Tf结合的铁对Hamp1调节的作用在Bmp6表达发生显著变化之前就已出现。总之，这些结果与调节Bmp6和Hamp1表达的新机制一致。
