Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 5, Pages 1324-1328Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0409409102
Keywords
reticuloendothelial cell; reticuloenclothelial system
Categories
Funding
- NIDDK NIH HHS [DK065064, DK56160, R01 DK056160-02, K01 DK065064, R01 DK056160, R01 DK056160-03, R01 DK056160-01, R01 DK056160-05, R01 DK056160-04] Funding Source: Medline
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Ferroportin 1 (FPN1) is transmembrane protein involved in iron homeostasis. In the duodenum, FIRM localizes to the basolateral surface of enterocytes where it appears to export iron out of the cell and into the portal circulation. FIRM is also abundantly expressed in reticuloendothelial macrophages of the liver, spleen, and bone marrow, suggesting that this protein serves as an iron exporter in cells that recycle iron from senescent red blood cells. To directly test the hypothesis that FPN1 functions in the export of iron after erythrophagocytosis, FPN1 was stably expressed in J774 mouse macrophages by using retroviral transduction, and release of Fe-59 after phagocytosis of Fe-59-labeled rat erythrocytes was measured. J774 cells overexpressing FPN1 released 70% more Fe-59 after erythrophagocytosis than control cells, consistent with a role in the recycling of iron from senescent red cells. Treatment of cells with the peptide hormone hepcidin, a systemic regulator of iron metabolism, dramatically decreased FPN1 protein levels and significantly reduced the efflux of Fe-59 after erythrophagocytosis. Subsequent fractionation of the total released Fe-59 into heme and nonheme compounds revealed that hepcidin treatment reduced the release of nonheme 59Fe by 50% and 25% from control and FPN1-overexpressing cells, respectively, but did not diminish efflux of Fe-59-heme. We conclude that FIRM is directly involved in the export of iron during erythrocyte-iron recycling by macrophages.
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