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Dietary iron absorption takes place at the apical membrane of mature enterocytes. Heme-bound iron is taken up by the heme receptor; non-heme-bound iron is imported into the cell by the divalent metal transporter protein
(DMT1) [3]. After enzymatic reduction from Fe3+ to Fe2+, iron can either be stored within the cell as ferritin, or transferred across the basolateral membrane into the blood by the iron regulated transporter 1 (IRGE1 or ferroportin) [4]. Ferroportin binds to plasma transferrin, and is available for distribution through the blood. Hephaestin is bound to the membrane and appears to assist ferroportin by oxidizing iron for loading onto transferrin in the plasma, thereby facilitating enterocyte iron release [5]. Hepcidin, a 20-25 amino acid hepatic peptide, also regulates intestinal iron absorption by inhibiting the release of iron into the plasma from the duodenum. Hepcidin binds to ferroportin molecules on the surface of duodenal enterocytes and encourages its degradation, thus inhibiting the export of iron from the enterocytes. It also regulates release of iron from liver stores and macrophages involved in the recycling of iron for hemoglobin. In normal iron homeostasis, an increase in plasma iron (eg after a meal or iron supplement) causes an increase in hepcidin release from the liver. These elevated hepcidin levels inhibit release of iron into the plasma from the duodenum, macrophages, and hepatocytes. As plasma iron is then consumed for hemoglobin synthesis, hepcidin levels also decrease, thereby completing the homeostasis loop [6].
 Image provided courtesy of Dr Hanspeter Nick, Basel, Switzerland.
In patients with hereditary hemochromatosis, increased iron absorption leads to a gradual accumulation of iron. The iron regulatory protein HFE has been implicated in this process [5]. Many cases of hemochromatosis may be due to hepcidin deficiency. Mice and humans with homozygous disruption of the HFE gene have inappropriately low expression of hepcidin mRNA in the liver, implicating HFE as a possible regulator of hepcidin[7].
Under conditions of normal iron homeostasis, transferrin-bound iron enters the cell by binding to transferrin receptors on the cell membrane, which are engulfed through endocytosis. Inside the endosome, iron is converted into hemosiderin, which can be released into the cytosol by a process of acidification. The transferrin receptors and apotransferrin (transferrin without iron) are recycled back to the cell surface. Triggered by the neutral pH of the blood, the receptor complex releases apotransferrin. The receptor is now available to bind to another transferrin molecule.
During the iron overloaded state, NTBI is taken up excessively by cells via an uncontrolled uptake mechanism (in the myocardium this is thought to involve calcium channels), leading to iron-overload pathologies in the liver, heart, and endocrine glands. Labile plasma iron is taken up initially by endocytic processes raising the cell labile iron pool. With sustained iron loading the metal also deposits as ferritin, which may eventually also transform into hemosiderin. When labile iron pool levels exceed the cell antioxidant capacity they evoke the formation of reactive oxygen species, which can cause cell damage by affecting lipids, proteins, and nucleic acids.
In response to increased intracellular iron levels, the liver synthesizes and releases hepcidin, which has a dual role. It stimulates increased iron storage by reticuloendothelial macrophages and decreases iron export from enterocytes [8]. Hepatocellular iron uptake is especially efficient, owing to the high number of transferrin receptors on the cell surface. When liver iron storage reaches critical levels, intracellular labile iron can promote damage of cellular organelles, such as mitochondria, by radical formation (oxidative stress) that can lead to cellular dysfunction and death. During conditions of iron loading, greatly increased erythropoiesis suppresses hepcidin production through an, as yet, unknown mechanism. Due to the low hepcidin levels, continued iron absorption leads to elevated plasma levels, transferrin saturation, and increased levels of NTBI. Hepcidin also has a ferroportin-mediated downregulating effect on the release of iron from cells. Therefore, if hepcidin decreases there is more 'free iron' in plasma [7, 9].
 One of the main roles of reticuloendothelial macrophages is in the recycling of iron from red blood cells. Reticuloendothelial macrophages remove iron from the blood mainly by phagocytosis of senescent red blood cells. They release their iron into the plasma through the iron export protein ferroportin. Released iron is oxidized into the ferric (Fe3+) state by ceruloplasmin, a reaction that allows the iron to bind to transferrin.
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