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Ferrata Storti Foundation
Haematologica 2019 Volume 104(4):678-689
Iron Metabolism & its Disorders
Gastrointestinal iron excretion and reversal of iron excess in a mouse model of inherited iron excess
Courtney J. Mercadante,1 Milankumar Prajapati,1 Jignesh H. Parmar,2 Heather L. Conboy,1 Miriam E. Dash,1 Michael A. Pettiglio,1 Carolina Herrera,1 Julia T. Bu,1 Edward G. Stopa, 1Pedro Mendes2 and Thomas B. Bartnikas1
1Department of Pathology and Laboratory Medicine, Brown University, Providence, RI and 2Center for Quantitative Medicine and Department of Cell Biology, University of Connecticut School of Medicine, Farmington, CT, USA
ABSTRACT
The current paradigm in the field of mammalian iron biology states that body iron levels are determined by dietary iron absorption, not by iron excretion. Iron absorption is a highly regulated process influ- enced by iron levels and other factors. Iron excretion is believed to occur at a basal rate irrespective of iron levels and is associated with processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Here we explore iron excretion in a mouse model of iron excess due to inherited transferrin deficiency. Iron excess in this model is attributed to impaired regulation of iron absorption leading to excessive dietary iron uptake. Pharmacological correction of transferrin deficiency not only nor- malized iron absorption rates and halted progression of iron excess but also reversed body iron excess. Transferrin treatment did not alter the half-life of 59Fe in mutant mice. 59Fe-based studies indicated that most iron was excreted via the gastrointestinal tract and suggested that iron-loaded mutant mice had increased rates of iron excretion. Direct measurement of urinary iron levels agreed with 59Fe-based predictions that urinary iron levels were increased in untreated mutant mice. Fecal ferritin levels were also increased in mutant mice relative to wild-type mice. Overall, these data suggest that mice have a significant capacity for iron excretion. We propose that further investigation into iron excretion is warranted in this and other models of perturbed iron homeostasis, as pharmacological targeting of iron excretion may represent a novel means of treatment for diseases of iron excess.
Introduction
Iron is an essential nutrient but toxic when present in excess. While body iron levels are determined in theory by a balance between absorption and excretion, the current paradigm in the field of iron biology states that the rate of absorption determines iron levels.1–5 Iron absorption is an orchestrated process regulated prominently by hepcidin, a hormone synthesized mainly by the liver which inhibits iron export from duodenal enterocytes and other types of cells. Hepcidin expression is suppressed by anemia, leading to increased absorption of iron, and stimulated by iron excess and inflammation, leading to decreased absorption. Hepcidin deficiency is central to common inherited diseases of iron excess such as hereditary hemochromatosis and β-thalassemia. Hemochromatosis is caused by mutations in genes required for hepcidin expression.6,7 β-thalassemia is caused by β-globin mutations leading to ineffective erythropoiesis, anemia, and hepcidin deficiency.8–10
In contrast to iron absorption, iron excretion is presumed to occur at a basal rate irrespective of iron deficiency or excess.1–5 Excretion is believed to reflect processes such as turnover of intestinal epithelium, blood loss, and exfoliation of dead skin. Renal iron excretion is considered a negligible factor in iron homeostasis. The liver
Correspondence:
THOMAS BARTNIKAS
thomas_bartnikas@brown.edu
Received: May 22, 2018. Accepted: November 7, 2018. Pre-published: November 8, 2018.
doi:10.3324/haematol.2018.198382
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/4/678
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