Ferroportin transporter

Non-heme iron exists in plant products and its bioavailability is compromised by the concurrent ingestion of tannins, phytates, soy, and other plant constituents, that decrease its solubility in the intestinal lumen. Bioavailability of non-heme iron is increased by concurrent ingestion of ascorbic acid and meat products. Nonheme iron is reduced from the ferric to the ferrous form in the intestinal lumen and transported into enterocytes via the divalent metal transporter (DMT-1). Once inside the enterocyte, iron from heme and nonheme sources is similarly transported through the cell and across the basolateral membrane by the ferroportin transporter in conjunction with the ferroxidase hephaestin after which it can be taken up by transferrin into the circulation. The regulation of iron across the basolateral membrane of the enterocyte is considered the most important aspect of iron absorption. 

The absorption efficiency of non-heme iron in particular is also inversely related to iron status. The factor responsible for communicating body iron status to the enterocyte to allow for the up- or downregulation of iron absorption remained elusive until recently, when the hormone hepcidin was identified. Hepcidin declines during iron deficiency, and its decline is associated with an increased production of the DMT-1 and ferroportin transporters in a rat model, although its exact mode of action is unknown. Hepcidin may also regulate iron absorption and retention or release of iron from body stores during conditions of enhanced erythropoiesis and inflammation. 

In the enterocyte as it enters the absorptive zone near to the villus tips, dietary iron is absorbed either directly as Fe(II) after reduction in the gastrointestinal tract by reductants like ascorbate, or after reduction of Fe(III) by the apical membrane ferrireductase Dcytb, via the divalent transporter Nramp2 (DCT1). Alternatively, haem is taken up at the apical surface, perhaps via a receptor, and is degraded by haem oxygenase to release Fe(II) into the same intracellular pool. The setting of IRPs (which are assumed to act as iron biosensors) determines the amount of iron that is retained within the enterocyte as ferritin, and that which is transferred to the circulation. This latter process is presumed to involve IREG 1 (ferroportin) and the GPI-linked hephaestin at the basolateral membrane with incorporation of iron into apotransferrin. (b) A representation of iron absorption in HFE-related haemochromatosis. 

Physiologically, body stores are maintained by extracting approximately 10% of the iron provided in a balanced diet and this corresponds to 1.5 mg each day for males and slightly more for females to compensate for pregnancy and menses. The trace element is derived from food by peptic digestion and after reduction the ferrous form crosses the enterocyte to be released at the serosal pole via the ferroportin-hepcidin mechanism to be transported, by plasma transferrin, to developing red cells in the marrow for haemoglobin synthesis. At the end of their life span effete erythrocytes are removed by the reticuloendothelial system in the spleen, bone marrow and the liver. 

Once absorbed, iron becomes part of the cellular iron pool, either stored as ferritin or transported across the basolateral membrane of the enterocyte into the circulation by an iron transporter called ferroportin 1. Hephaestin, a basolateral membrane ferroxidase, oxidizes the ferrous iron back to its ferric form, thus completing the absorption process (Harrison and Bacon, 2003). 

Figure 31-1. A schematic model of HFE regulation of iron transport in duodenal ente-rocytes. A and B correspond to villus and cryptal enterocytes, respectively. As noted, HFE lies at the center of regulation of iron absorption through its role in sensing body iron stores in the villus enterocyte. It communicates this information to the crypt ente-rocyte indirectly through regulation of development of ferroportin and DMT-1. Reprinted with permission from Parkkila et al. (2001). 2001, American Gastroenterological Association.

Once inside the mucosal cell, iron then has to be transported across the membrane to serum transferrin. This appears to take place via the Iregl transporter protein (also known as ferroportin 1 or MTPl). Iregl is a transmembrane protein located at the basolateral membrane of the cell that has been shown to be involved in iron uptake. Oxidation of Iregl-bound ferrous iron and its release to transferrin is likely to be enhanced by the membrane-bound multicopper ferroxidase hephaestin. This protein is 50% identical to ceruloplasmin, a soluble protein identified as having a possible role in iron loading of transferrin see Copper Proteins Oxidases). Mutation of hephaestin in mice leads to a build up of iron in duodenal cells and overall iron deficiency in the body. ... 

Several other iron metabolism proteins contain IREs, including ferroportin, an iron exporter, the erythrocyte form of aminolevulinic acid synthase, an enzyme important in heme biosynthesis, an alternatively spliced transcript of the iron transporter DMTl, and mammalian mitochondrial aconitase. The importance of these IREs in regulation of these transcripts is the subject of ongoing research. 

The mucosal cells of the proximal small bowel regulate iron absorption. Dietary and administered iron is actively transported into the gut mucosal cell, probably involving a protein DMTl though the precise details have not been established. Two other proteins, hephaestin and ferroportin 1, appear to be involved in intracellular transport and release into the plasma respectively. Regulation of absorption may involve one or more of (1) control of mucosal uptake (2) retention of iron in storage form in the mucosal cell and (3) transfer from the mucosal cell to the plasma. Increased erythropoietic activity also stimulates increased absorption. Iron that is not needed by the body may be bound to a protein (apoferritin) as ferritin and lost into the gut lumen when the mucosal cell is shed (2-3 days). Iron is eUminated at a near constant rate in the faeces of healthy people. 

Iron transporters DMTl Ferroportin Membrane Fe " inward transporter Membrane Fe " outward transporter... 

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