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.