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Iron is required in a variety of essential processes in the body. In this review, we focus on iron transport in the brain and the role of the divalent metal transporter 1 (DMT1) vital for iron uptake in most cells. DMT1 locates to cellular membranes and endosomal membranes, where it is a key player in non-transferrin bound iron uptake and transferrin-bound iron uptake, respectively. Four isoforms of DMT1 exist, and their respective characteristics involve a complex cell-specific regulatory machinery all controlling iron transport across these membranes. This complexity reflects the fine balance required in iron homeostasis, as this metal is indispensable in many cell functions but highly toxic when appearing in excess. DMT1 expression in the brain is prominent in neurons. Of serious dispute is the expression of DMT1 in non-neuronal cells. Recent studies imply that DMT1 does exist in endosomes of brain capillary endothelial cells denoting the blood-brain barrier. This supports existing evidence that iron uptake at the BBB occurs by means of transferrin-receptor mediated endocytosis followed by detachment of iron from transferrin inside the acidic compartment of the endosome and DMT1-mediated pumping iron into the cytosol. The subsequent iron transport across the abluminal membrane into the brain likely occurs by ferroportin. The virtual absent expression of transferrin receptors and DMT1 in glial cells, i.e., astrocytes, microglia and oligodendrocytes, suggest that the steady state uptake of iron in glia is much lower than in neurons and/or other mechanisms for iron uptake in these cell types prevail.

The Belgrade rat is an animal model of divalent metal transporter 1 (DMT1) deficiency. This strain originates from an X-irradiation experiment first reported in 1966. Since then, the Belgrade rat's pathophysiology has helped to reveal the importance of iron balance and the role of DMT1. This review discusses our current understanding of iron transport homeostasis and summarizes molecular details of DMT1 function. We describe how studies of the Belgrade rat have revealed key roles for DMT1 in iron distribution to red blood cells as well as duodenal iron absorption. The Belgrade rat's pathology has extended our knowledge of hepatic iron handling, pulmonary and olfactory iron transport as well as brain iron uptake and renal iron handling. For example, relationships between iron and manganese metabolism have been discerned since both are essential metals transported by DMT1. Pathophysiologic features of the Belgrade rat provide us with a unique and interesting animal model to understand iron homeostasis.

Belgrade rats inherit microcytic, hypochromic anemia as an autosomal recessive trait (gene symbol b). Erythrocytes and tissue are iron deficient in the face of elevated TIBC (total iron binding capacity) and percent iron saturation; iron injections increased the number of erythrocytes but their appearance remained abnormal. We have investigated iron supplements to improve husbandry of b/b rats and to learn more about the underlying defect and its tissue distribution. Weekly i.m. (intramuscular) injections of iron-dextran (Imferon at 30 mg kg-1) improved the anemia but did not alter the red cell morphology. Certain diets also improved the health of b/b rats when compared to standard rat chows by the criteria of weight, survival to adulthood, hematology and reproduction. The critical nutritional factor turned out to be iron bioavailability, with ferrous iron added to the diet improving the health of Belgrade rats without affecting the underlying erythroid defect. Tissue iron measurements after dietary or parenteral supplementation confirmed the iron deficient status of untreated b/b rats and established that dietary ferrous iron partially relieved this deficiency, with injections leading to greater amounts of tissue iron. Serum iron and TIBC were also found to be elevated in untreated b/b rats, with dietary supplementation decreasing but not eliminating the elevation in TIBC. These studies indicate that iron supplements can improve the health of b/b rats without altering the underlying defect and also suggest that the mutation could alter iron uptake in the GI (gastrointestinal) tract.