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ABSTRACT: 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 Nramp 1, DMT 1, HFE, FPN 1, CD 163, 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.
KEY WORDS: CD163, DMT1, ferroportin1, hepcidin, HFE, Nrampl.
I. INTRODUCTION
One of the most distinguishing features of iron metabolism is the degree to which body iron is conserved. Of the typical 3 to 4 g of iron contained in the normal adult human, only about 0.03% (or -1 mg) is lost per day, mainly the result of obligatory losses of exfoliated mucosal cells, bile, and extravasated red cells. To replace these basal losses and remain in iron balance, the body must absorb a roughly equivalent amount of iron from the diet. This relatively small daily exchange of iron between body and environment contrasts sharply with the comparatively large exchange of this metal between internal organs. For example, each day the bone marrow utilizes approximately 24 mg of iron to produce over 200 billion new erythrocytes. To meet the demand for heme production necessary for erythropoiesis, iron must be recycled from senescent red cells; this process is carried out by macrophages of the reticuloendothelial system (RES). Despite this critical role of the RES in body iron conservation, iron recycling by the RE cell has remained one of the least well-understood areas of iron metabolism (Risen, 1990). However, in the last decade five new genes involved in iron metabolism have been discovered: Nrampl (Vidal et al., 1993), HFE (Feder et al., 1996), DMT1 (Fleming et al., 1997; Gunshin...