A compartmental model of iron regulation in the mouse

Lao, Bert J.; Kamei, Daniel T.

doi:10.1016/j.jtbi.2006.06.033

Cited by 11 publications

(9 citation statements)

References 57 publications

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“…Systems biological approaches are required to fully understand the dynamics of this complex network. So far mathematical models only described subsystems of iron metabolism, including liver iron metabolism [43, 44], intestinal iron absorption [45], iron release from macrophages [46] or storage of iron in ferritin [47]. To describe iron metabolism on a systemic level, Lopes et al derived a whole-body model, which integrated iron fluxes between blood and different organs [40].…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2017

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“…J. Lao and D. T. Kamei developed a simple compartmental model of iron homeostasis calibrated to mouse data [84]. The model consists of five compartments, each denoting the amount of iron at a specific location or in a particular state: hepatocyte, FeTf (diferric transferrin), RBC (red blood cells), NTBI (non-transferrin-bound-iron), and macrophage.…”

Section: A Systems Biology Approach To Iron Metabolismmentioning

confidence: 99%

A Systems Biology Approach to Iron Metabolism

Chifman

Laubenbacher

Torti

2014

Advances in Experimental Medicine and Biology

112

122

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Iron is critical to the survival of almost all living organisms. However, inappropriately low or high levels of iron are detrimental and contribute to a wide range of diseases. Recent advances in the study of iron metabolism have revealed multiple intricate pathways that are essential to the maintenance of iron homeostasis. Further, iron regulation involves processes at several scales, ranging from the subcellular to the organismal. This complexity makes a systems biology approach crucial, with its enabling technology of computational models based on a mathematical description of regulatory systems. Systems biology may represent a new strategy for understanding imbalances in iron metabolism and their underlying causes.

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“…The dotted line represents the simulation when only the diet was adjusted, the bold line is the model simulation when both diet and hepcidin synthesis rate were adjusted. Filled circles represent the data from [17] (vertical bars represent one standard deviation). The abscissa represents the proportion of total injected 59 Fe, the ordinate is time after injection.…”

Section: Iron-rich Dietmentioning

confidence: 99%

Modeling the dynamics of mouse iron body distribution: hepcidin is necessary but not sufficient

Parmar

Davis

Shevchuk

et al. 2016

Preprint

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Background: Iron is an essential element of most living organisms but is a dangerous substance when poorly liganded in solution. The hormone hepcidin regulates the export of iron from tissues to the plasma contributing to iron homeostasis and also restricting its availability to infectious agents. Disruption of iron regulation in mammals leads to disorders such as anemia and hemochromatosis, and contributes to the etiology of several other diseases such as cancer and neurodegenerative diseases. Here we test the hypothesis that hepcidin alone is able to regulate iron distribution in different dietary regimes in the mouse using a computational model of iron distribution calibrated with radioiron tracer data. Results: A model was developed and calibrated to the data from adequate iron diet, which was able to simulate the iron distribution under a low iron diet. However simulation of high iron diet shows considerable deviations from the experimental data. Namely the model predicts more iron in red blood cells and less iron in the liver than what was observed in experiments. Conclusions: These results suggest that hepcidin alone is not sufficient to regulate iron homeostasis in high iron conditions and that other factors are important. The model was able to simulate anemia when hepcidin was increased but was unable to simulate hemochromatosis when hepcidin was suppressed, suggesting that in high iron conditions additional regulatory interactions are important.

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A compartmental model of iron regulation in the mouse

Cited by 11 publications

References 57 publications

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

A Systems Biology Approach to Iron Metabolism

Modeling the dynamics of mouse iron body distribution: hepcidin is necessary but not sufficient

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