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Abstract
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.
Highlights
Iron is an essential element for the organism
We considered that the export of iron from peripheral organs is controlled by the iron exporter Fpn which is predominantly located at the plasma membrane of three cell types: duodenal enterocytes, macrophages and hepatocytes
The model supports the important role of hepcidin for the inflammatory response but shows that transcriptional regulation of Fpn after an inflammatory insult is required to efficiently establish hypoferremia
Summary
Iron is an essential element for the organism. It plays a critical role in oxygen transport, DNA synthesis, mitochondrial energy metabolism and as a cofactor of numerous enzymes [1, 2]. Excess free iron catalyzes reactions that result in the formation of reactive oxygen species and oxidative stress. Iron homeostasis must be maintained within a narrow range to provide sufficient iron for cellular function while preventing the generation of oxidative stress [3]. Systemic iron homeostasis is predominantly controlled by the interaction of the liver produced hormone hepcidin with its receptor, the iron transporter ferroportin (Fpn), resulting in the degradation of Fpn [4,5,6,7]. Fpn is the only known cellular iron exporter [8, 9]. Iron release from cells through Fpn requires the ferroxidases ceruloplasmin and/or hephaestin [10,11,12]
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