Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.
Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.
复制标题
在饮食中铁超负荷和急性炎症过程中对全身铁调节进行建模：肝素独立机制的作用。
DOI：
10.1371/journal.pcbi.1005322
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发表时间：
2017-01
影响因子：
4.3
通讯作者：
Legewie S
中科院分区：
文献类型：
--
作者：
Enculescu M;Metzendorf C;Sparla R;Hahnel M;Bode J;Muckenthaler MU;Legewie S
全身性铁水平必须维持在生理浓度，以预防与缺铁或铁负荷过重相关的疾病。在这一过程中起着关键作用的是铁蛋白，它是唯一已知的哺乳动物跨膜铁输出器，它将十二指肠肠细胞、肝细胞或铁循环巨噬细胞中的铁释放到血流中。铁转运蛋白的表达受到转录和转录后机制的严格控制，这些机制通过细胞自主机制和系统机制对缺氧、缺铁、血红素铁和炎症信号做出反应。在全身水平上，铁调节荷尔蒙海普西丁在这些信号的响应下从肝脏释放，与铁蛋白结合并触发其降解。单独的铁蛋白调控机制的相对重要性以及它们在系统水平上的相互作用尚不完全清楚。在这里，我们建立了一个系统性铁调节的数学模型。它结合了器官铁库的动态以及海普西丁/铁门蛋白系统的调节。我们通过对饮食铁超载和/或炎症挑战的小鼠铁反应的时间分辨测量来校准和验证该模型。该模型表明，炎症主要通过减少细胞内铁蛋白转录来减少血流中的铁量，而不是通过海普西丁依赖的铁蛋白失稳来减少。相反，海普西丁对铁转运蛋白的调节是铁稳态的主要机制，以应对大范围饮食中铁含量的变化。该模型进一步揭示，在很高的膳食铁水平下，必须考虑额外的动态平衡机制，包括肠道对营养性铁的摄取饱和以及循环中的非转铁蛋白结合的铁进入肝脏的摄取。综上所述，我们的模型定量描述了全身性铁代谢，并为额外的铁蛋白非依赖性稳态机制产生了实验上可测试的预测。铁在许多生理过程中的重要性取决于它参与还原-氧化反应的能力。如果细胞和组织没有适当地管理游离铁的浓度，这种特性也会导致潜在的毒性。因此，多细胞生物进化出复杂的调节机制来控制全身的铁水平。一个核心的调节机制是荷尔蒙海普西丁与铁出口蛋白铁的结合，铁蛋白控制着铁进入血浆的主要流量。在这里，我们提出了一个数学模型，该模型根据实验数据进行了拟合和验证，以模拟饮食变化和/或炎症状态下不同器官中的铁含量，或者海普西丁/铁蛋白调节系统的遗传扰动。我们发现，海普西丁介导的铁蛋白调控是必要的，但不足以定量解释我们的几个实验结果。因此，必须在模型中包括进一步的调节机制，以复制降低的血清铁水平，以应对炎症，在铁超载的情况下铁在肝脏中优先积累，或在饮食铁水平非常高的情况下维持生理血清铁浓度。我们得出结论，不依赖于海普西丁的机制在维持全身铁稳态中起着重要作用。
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. The importance of iron in many physiological processes relies on its ability to participate in reduction-oxidation reactions. This property also leads to potential toxicity if concentrations of free iron are not properly managed by cells and tissues. Multicellular organisms therefore evolved intricate regulatory mechanisms to control systemic iron levels. A central regulatory mechanism is the binding of the hormone hepcidin to the iron exporter ferroportin, which controls the major fluxes of iron into blood plasma. Here, we present a mathematical model that is fitted and validated against experimental data to simulate the iron content in different organs following dietary changes and/or inflammatory states, or genetic perturbation of the hepcidin/ferroportin regulatory system. We find that hepcidin mediated ferroportin control is essential, but not sufficient to quantitatively explain several of our experimental findings. Thus, further regulatory mechanisms had to be included in the model to reproduce reduced serum iron levels in response to inflammation, the preferential accumulation of iron in the liver in the case of iron overload, or the maintenance of physiological serum iron concentrations if dietary iron levels are very high. We conclude that hepcidin-independent mechanisms play an important role in maintaining systemic iron homeostasis.