A Computational Model of Liver Iron Metabolism

dc.contributorVirginia Techen
dc.contributor.authorMitchell, Simonen
dc.contributor.authorMendes, Pedroen
dc.date.accessed2014-07-02en
dc.date.accessioned2014-07-03T13:01:35Zen
dc.date.available2014-07-03T13:01:35Zen
dc.date.issued2013-11-07en
dc.description.abstractIron 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.en
dc.description.sponsorshipSM thanks the BBSRC and the University of Manchester for funding through the Manchester Doctoral Training Centre for Integrative Systems Biology. PM thanks the BBSRC (grant BB/J019259/1) and the NIH (grant R01 GM080219) for funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en
dc.identifier.citationMitchell S, Mendes P (2013) A Computational Model of Liver Iron Metabolism. PLoS Comput Biol 9(11): e1003299. doi:10.1371/journal.pcbi.1003299en
dc.identifier.doihttps://doi.org/10.1371/journal.pcbi.1003299en
dc.identifier.issn1553-7358en
dc.identifier.urihttp://hdl.handle.net/10919/49306en
dc.identifier.urlhttp://www.ploscompbiol.org/article/info%3Adoi%2F10.1371%2Fjournal.pcbi.1003299en
dc.language.isoen_USen
dc.publisherPublic Library of Scienceen
dc.rightsCreative Commons CC0 1.0 Universal Public Domain Dedicationen
dc.rights.urihttp://creativecommons.org/publicdomain/zero/1.0/en
dc.subjectCell metabolismen
dc.subjectFerritinen
dc.subjectIronen
dc.subjectIron deficiencyen
dc.subjectMutationen
dc.subjectNetwork analysisen
dc.subjectProtein metabolismen
dc.subjectSimulation and modelingen
dc.titleA Computational Model of Liver Iron Metabolismen
dc.title.serialPlos Computational Biologyen
dc.typeArticle - Refereeden

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