A computational model of liver iron metabolism.
A computational model of liver iron metabolism.
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DOI：
10.1371/journal.pcbi.1003299
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发表时间：
2013
影响因子：
4.3
通讯作者：
Mendes P
中科院分区：
文献类型：
--
作者：
Mitchell S;Mendes P
由于铁的氧化还原特性，铁对所有已知的生命都是必不可少的；然而，这些相同的特性也可能导致铁在过载时通过产生活性氧物种而产生毒性。维持铁的安全水平需要强大的系统和细胞控制，而肝脏似乎是这种调节的主要位置。铁调节失调与许多疾病有关，随着我们对铁代谢的了解的提高，与铁有关的疾病的名单也越来越多。最近的事态发展使人们对铁在体内的命运有了更多的了解，并产生了其新陈代谢的详细地图；然而，在系统层面上对其组成部分如何相互作用以产生严格调控的定量理解仍然难以捉摸。本文提出了一个包含核心调节成分的人体肝脏铁代谢的力学计算模型。它是基于已知的调控机制及其动力学特性而构建的，这些机制是从几个出版物获得的。然后，通过将其结果与之前发表的生理数据进行比较，该模型得到了定量验证，并且它能够重现多个实验结果。将口服铁剂后的时间进程模拟与临床时间进程研究进行比较，发现该模拟重建了系统对铁挑战的反应的动力学和时间尺度。血色病的疾病状态模拟是通过改变模仿人类血色病基因(HFE)突变的单一反应参数来创建的。该模拟提供了对这种疾病中出现的肝脏铁超载的定量了解。这一模型支持和补充了对肝脏作为铁传感器的作用的理解，并为进一步建模提供了一个框架，包括用于识别有价值的药物靶点的模拟和实验设计，以进一步提高我们对这一系统的知识。铁是健康生活所必需的营养物质，但过量则会导致身体虚弱，甚至致命。人类最常见的遗传疾病是由突变引起的血色素沉着症，它会导致肝脏中的铁超载。事实上，肝脏在铁的调节中起着核心作用。最近，人们发现了越来越多与铁代谢相关的分子的细节，但对于它们如何协同工作并调节铁水平(在健康人中)或未能做到这一点(在疾病中)，仍缺乏了解。我们提出了一个调节肝脏铁代谢的数学模型，该模型解释了其动力学，并允许进一步的假设被制定出来，并在以后的实验中进行测试。重要的是，该模型准确地再现了健康的肝铁稳态，并模拟了血色病，显示了致病突变是如何导致铁超载的。我们研究了如何最好地控制铁的调节，并确定了可以成为治疗铁超载新药靶点的反应。该模型为研究铁代谢提供了一个虚拟实验室，并提高了对肝脏感知和控制铁水平的方法的理解。
Iron is essential for all known life due to its redox properties; however, these same properties can also lead to its toxicity in overload through the production of reactive oxygen species. Robust systemic and cellular control are required to maintain safe levels of iron, and the liver seems to be where this regulation is mainly located. Iron misregulation is implicated in many diseases, and as our understanding of iron metabolism improves, the list of iron-related disorders grows. Recent developments have resulted in greater knowledge of the fate of iron in the body and have led to a detailed map of its metabolism; however, a quantitative understanding at the systems level of how its components interact to produce tight regulation remains elusive. A mechanistic computational model of human liver iron metabolism, which includes the core regulatory components, is presented here. It was constructed based on known mechanisms of regulation and on their kinetic properties, obtained from several publications. The model was then quantitatively validated by comparing its results with previously published physiological data, and it is able to reproduce multiple experimental findings. A time course simulation following an oral dose of iron was compared to a clinical time course study and the simulation was found to recreate the dynamics and time scale of the systems response to iron challenge. A disease state simulation of haemochromatosis was created by altering a single reaction parameter that mimics a human haemochromatosis gene (HFE) mutation. The simulation provides a quantitative understanding of the liver iron overload that arises in this disease. This model supports and supplements understanding of the role of the liver as an iron sensor and provides a framework for further modelling, including simulations to identify valuable drug targets and design of experiments to improve further our knowledge of this system. Iron is an essential nutrient required for healthy life but, in excess, is the cause of debilitating and even fatal conditions. The most common genetic disorder in humans caused by a mutation, haemochromatosis, results in an iron overload in the liver. Indeed, the liver plays a central role in the regulation of iron. Recently, an increasing amount of detail has been discovered about molecules related to iron metabolism, but an understanding of how they work together and regulate iron levels (in healthy people) or fail to do it (in disease) is still missing. We present a mathematical model of the regulation of liver iron metabolism that provides explanations of its dynamics and allows further hypotheses to be formulated and later tested in experiments. Importantly, the model reproduces accurately the healthy liver iron homeostasis and simulates haemochromatosis, showing how the causative mutation leads to iron overload. We investigate how best to control iron regulation and identified reactions that can be targets of new medicines to treat iron overload. The model provides a virtual laboratory for investigating iron metabolism and improves understanding of the method by which the liver senses and controls iron levels.
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