No abstract

Ferroportin 1 (FPN1) is transmembrane protein involved in iron homeostasis. In the duodenum, FPN1 localizes to the basolateral surface of enterocytes where it appears to export iron out of the cell and into the portal circulation. FPN1 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 59 Fe after phagocytosis of 59 Fe-labeled rat erythrocytes was measured. J774 cells overexpressing FPN1 released 70% more 59 Fe 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 59 Fe after erythrophagocytosis. Subsequent fractionation of the total released 59 Fe into heme and nonheme compounds revealed that hepcidin treatment reduced the release of nonheme 59 Fe by 50% and 25% from control and FPN1-overexpressing cells, respectively, but did not diminish efflux of 59 Fe-heme. We conclude that FPN1 is directly involved in the export of iron during erythrocyte-iron recycling by macrophages. reticuloendothelial cell ͉ reticuloendothelial system A pproximately two-thirds of total body iron in the adult human is present in hemoglobin in circulating red blood cells. Mature erythrocytes circulate until senescent or damaged and are then phagocytosed predominantly by reticuloendothelial macrophages of the liver, bone marrow, and spleen. After erythrophagocytosis, hemoglobin is proteolytically degraded, and the resultant heme moiety is oxidatively cleaved to release free iron, which is then either stored within the macrophage or released into the circulation. This recycling of iron from senescent red cells supplies the bone marrow with Ϸ20 mg of iron per day for new red cell synthesis (1).Several lines of evidence implicate the involvement of the recently identified protein ferroportin 1 (FPN1) in iron recycling by the macrophage. FPN1, also known as IREG-1 and MTP-1, was initially identified as an iron-export protein located on the basolateral membrane of duodenal enterocytes (2-4). The abundant expression of FPN1 in reticuloendothelial macrophages of the liver, bone marrow, and splenic red pulp (5) suggests that it plays a similar iron-export role in macrophages as well. Genetic evidence for this proposed function is provided by a growing number of hemochromatosis patients identified with mutations in FPN1 (reviewed in ref. 6). The distinguishing clinical feature of these patients is iron accumulation in liver macrophages (Kupffer cells). Studies of cultured macrophages, which show marked increases in FPN1 after erythrophagocytosis ...

Iron and its homeostasis are intimately tied to the inflammatory response. The adaptation to iron deficiency, which confers resistance to infection and improves the inflammatory condition, underlies what is probably the most obvious link: the anemia of inflammation or chronic disease. A large number of stimulatory inputs must be integrated to tightly control iron homeostasis during the inflammatory response. In order to understand the pathways of iron trafficking and how they are regulated, this chapter will present a brief overview of iron homeostasis. A major focus will be on the regulation of the peptide hormone hepcidin during the inflammatory response and how its function contributes to the process of iron withdrawal. The review will also summarize new and emerging information about other iron metabolic regulators and effectors that contribute to the inflammatory response. Potential benefits of treatment to ameliorate the hypoferremic condition promoted by inflammation will also be considered.

The understanding of iron metabolism at the molecular level has been enormously expanded in recent years by new findings about the functioning of transferrin, the transferrin receptor and ferritin. Other recent developments include the discovery of the hemochromatosis gene HFE, identification of previously unknown proteins involved in iron transport, divalent metal transporter 1 and stimulator of Fe transport, and expanded insights into the regulation and expression of proteins involved in iron metabolism. Interactions among principal participants in iron transport have been uncovered, although the complexity of such interactions is still incompletely understood. Correlated efforts involving techniques and concepts of crystallography, spectroscopy and molecular biology applied to cellular processes have been, and should continue to be, particularly revealing.

Comprised mainly of monocytes and tissue macrophages, the reticuloendothelial system (RES) plays two major roles in iron metabolism: it recycles iron from senescent red blood cells and it serves as a large storage depot for excess iron. Although iron recycling by the RES represents the largest pathway of iron efflux in the body, the precise mechanisms involved have remained elusive. However, studies characterizing the function and regulation of Nramp1, DMT1, HFE, FPN1, CD163, and hepcidin are rapidly expanding our knowledge of the molecular aspects of RE iron handling. This review summarizes fundamental physiological and biochemical aspects of iron metabolism in the RES and focuses on how recent studies have advanced our understanding of these areas. Also discussed are novel insights into the molecular mechanisms contributing to the abnormal RE iron metabolism characteristic of hereditary hemochromatosis and the anemia of chronic disease.