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Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms

机译:在膳食铁超负荷和急性炎症过程中建模全身铁调节:铁调素独立机制的作用。

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摘要

Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional ferroportin-independent homeostasis mechanisms.
机译:全身铁水平必须保持在生理浓度,以防止与铁缺乏或铁超负荷有关的疾病。在这个过程中的关键作用是铁转运蛋白,这是唯一已知的哺乳动物跨膜铁输出,它从十二指肠肠上皮细胞,肝细胞或铁回收巨噬细胞中释放铁到血流中。响应于缺氧,铁缺乏,血红素铁和炎性线索的应答,通过细胞自主和全身机制,铁转运蛋白的表达受到转录和转录后机制的严格控制。在全身水平,铁调节激素铁调素响应这些提示而从肝脏释放出来,与铁转运蛋白结合并触发其降解。单个铁转运蛋白控制机制的相对重要性及其在系统水平上的相互作用尚不完全清楚。在这里,我们建立了系统铁调节的数学模型。它结合了器官铁池的动力学以及铁调素/铁转运蛋白系统的调节作用。我们用时间分辨测量铁对饮食中铁负荷过高和/或发炎的小鼠的铁反应进行了校准和验证。该模型表明炎症主要通过减少细胞内铁转运蛋白的转录来减少血流中的铁量,而不是铁调素依赖性铁转运蛋白的去稳定作用。相比之下,铁调素通过铁调素的调节是铁稳态的主要机制,该铁稳态是在饮食中铁含量变化很大的情况下对改变铁饮食的反应。该模型进一步表明,在非常高的饮食铁水平下,必须考虑其他稳态机制,包括肠道对营养铁的摄取饱和以及循环的,与运铁蛋白结合的循环铁向肝脏的摄取。综上所述,我们的模型定量描述了全身铁代谢,并生成了其他铁转运蛋白非依赖性稳态机制的实验可测预测。

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