Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4
Iron transferrin regulates hepcidin synthesis in primary hepatocyte culture through hemojuvelin and BMP2/4
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DOI：
10.1182/blood-2007-04-087593
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发表时间：
2007-09-15
期刊：
影响因子：
20.3
通讯作者：
Ganz, Tomas
中科院分区：
文献类型：
--
作者：
Lin, Lan;Valore, Erika V.;Ganz, Tomas
肽激素铁调素是全身铁稳态的主要调节剂。我们研究了铁刺激铁调素产生的途径。在摄入 65 毫克铁的人类中，转铁蛋白饱和度的增加先于尿铁调素排泄量的增加几个小时。尿铁调素浓度的增加与转铁蛋白饱和度的增加成正比。矛盾的是，在先前对原代肝细胞和细胞系的研究中，没有观察到铁调素对铁或铁转铁蛋白的反应。我们现在报道，新鲜分离的小鼠原代肝细胞通过增加铁调素 mRNA 对全转铁蛋白而非脱铁转铁蛋白做出反应。铁调素增加并非由于转铁蛋白制剂被内毒素污染所致，内毒素是铁调素合成的有效病理刺激物。使用该培养系统，我们发现全转铁蛋白浓度通过血幼素/BMP2/4依赖性途径调节铁调素mRNA浓度。尽管已知 BMP9 在肝脏中表达并有效增加铁调素 mRNA 的基础浓度，但它不与血幼素相互作用，并且干扰其信号通路不会影响铁调节。新鲜的原代肝细胞构成了通过生理铁刺激调节铁调素的充分系统，并将极大地促进铁稳态主要疾病的研究。
The peptide hormone hepcidin is the principal regulator of systemic iron homeostasis. We examined the pathway by which iron stimulates the production of hepcidin. In humans who ingested 65 mg of iron, the increase in transferrin saturation preceded by hours the increase in urinary hepcidin excretion. Increases in urinary hepcidin concentrations were proportional to the increment in transferrin saturation. Paradoxically, in previous studies in primary hepatocytes and cell lines, hepcidin response to iron or iron transferrin was not observed. We now report that freshly isolated murine primary hepatocytes responded to holotransferrin but not apotransferrin by increasing hepcidin mRNA. Hepcidin increase was not due to contamination of the transferrin preparations by endotoxin, a potent pathologic stimulus of hepcidin synthesis. Using this culture system, we showed that holotransferrin concentrations regulate hepcidin mRNA concentrations through a hemojuvelin/BMP2/4-dependent pathway. Although BMP9 is known to be expressed in the liver and potently increased the basal concentrations of hepcidin mRNA, it did not interact with hemojuvelin, and interference with its signaling pathway did not affect iron regulation. Fresh primary hepatocytes constitute a sufficient system for the regulation of hepcidin by physiologic iron stimuli and will greatly facilitate studies of major disorders of iron homeostasis.