title: Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms.
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.
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Mihaela
authors.initials: M
authors.lastname: Enculescu
authors.affiliation: Pediatric Oncology, Hematology & Immunology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, Heidelberg University, Heidelberg, Germany.
authors.forename: Christoph
authors.identifier: 0000-0003-3891-2809
authors.initials: C
authors.lastname: Metzendorf
authors.affiliation: Molecular Medicine Partnership Unit, Heidelberg University, Heidelberg, Germany.
authors.forename: Richard
authors.initials: R
authors.lastname: Sparla
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hahnel
authors.affiliation: Department of Gastroenterology, Hepatology and Infectious Diseases, Medical Faculty, University Hospital, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Bode
authors.affiliation: Pediatric Oncology, Hematology & Immunology, University Hospital Heidelberg, Heidelberg, Germany.|Molecular Medicine Partnership Unit, Heidelberg University, Heidelberg, Germany.
authors.forename: Martina U
authors.initials: MU
authors.lastname: Muckenthaler
authors.affiliation: Institute of Molecular Biology, Mainz, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Legewie
mesh_terms: D064451:Hepcidins / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism*; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000378:metabolism*; D053858:Metabolic Networks and Pathways; D008954:Models, Biological
chemical_list: D064451:Hepcidins; D007501:Iron