Yamaji, S; (2006) Molecular mechanisms and regulation of iron transport. Doctoral thesis , UCL (University College London).

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Abstract

Iron is an essential micronutrient for almost all the organisms, yet toxic in excess. Because there is no physiological mechanism to excrete iron, absorption is tightly regulated. In mammals, absorption takes place mainly in upper part of duodenum, and exact mechanisms are still unclear. In the past 5 years, a number of proteins involved in iron absorption has been identified and characterised. Divalent metal transporter 1 (DMT1, also known as Nramp2, DCT1, and SLC11A2) is the only known importer of inorganic iron into the body, and iron regulated transporter 1 (IREG1, also known as ferroportin, and MTP1) has been characterised as the iron exporter out of the enterocytes. The regulatory mechanisms of iron absorption are still unknown, though it is influenced by dietary iron, body iron store, and erythropoiesis. The level of other metals, such as zinc and copper, is also known to influence iron absorption. In thesis Caco-2 TC7 cells were used as a model of human intestine to investigating the possible regulatory mechanism of iron uptake by dietary metals (iron, copper, and zinc), and humoral signal from body store. Cells were cultured in plates for 21 days. For the final 24 h of the culture period, metals (iron, copper, and zinc) or human synthetic hepcidin (humoral signal) was added to the basolateral medium. At the end of the incubation period cells were used for analysis of changes in transporter gene expression. Caco-2 cells were also cultured in transwell, and used to measure 55Fe transport across the cell monolayers. Following exposure to iron, apical transporter, DMT1, was down regulated, whereas basolateral iron transporter IREG1 expression was unaffected. Interestingly gene expression of Hephaestin, which co-work with IREG1 at basolateral surface of the cell, was also down regulated. Copper, and zinc also down regulated DMT1 and hephaestin expression, as well as apical zinc transporter Zip1 in Caco-2 TC7 cells. Interestingly, exposure to copper and zinc significantly up regulated the expression of IREG1. Iron uptake across the apical membrane of Caco-2 cells was significantly decreased by exposure to hepcidin, whereas efflux across the basolateral membrane was unaffected by hepcidin treatment. In agreement with the transport data, the gene expression of DMT1 was decreased by hepcidin treatment and expression of IREG1 was unaffected. Additionally, the effect of iron (hemin) in macrophages was also investigated and found that their responses do not correspond to intestine.

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