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

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.Author Summary: 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.