Molecular pathogenesis of iron overload

Despite important advances in the understanding of copper secretion and excretion, the molecular components of intestinal copper absorption remain a mystery. DMT1, also known as Nramp2 and DCT1, is the transporter responsible for intestinal iron uptake. Electrophysiological evidence suggests that DMT1 can also be a copper transporter. Thus we examined the potential role of DMT1 as a copper transporter in intestinal Caco-2 cells. Treatment of cells with a DMT1 antisense oligonucleotide resulted in 80 and 48% inhibition of iron and copper uptake, respectively. Cells incorporated considerable amounts of copper as Cu1+, whereas Cu2+ transport was about 10-fold lower. Cu1+inhibited apical Fe2+ transport. Fe2+, but not Fe3+, effectively inhibited Cu1+ uptake. The iron content of the cells influenced both copper and iron uptake. Cells with low iron content transported fourfold more iron and threefold more copper than cells with high iron content. These results demonstrate that DMT1 is a physiologically relevant Cu1+ transporter in intestinal cells, indicating that intestinal absorption of copper and iron are intertwined.

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“…32). The transporter DMT1 (also called DCT1 and Nramp2) mediates the uptake phase of intestinal iron absorption.…”

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confidence: 99%

DMT1, a physiologically relevant apical Cu¹⁺transporter of intestinal cells

Arredondo

Muñoz

Mura

et al. 2003

American Journal of Physiology-Cell Physiology

235

184

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“…I ron absorption is regulated by several factors, including the level of body iron stores (via the stores regulator), the rate of erythropoiesis (via the erythroid regulator), and hypoxia. [1][2][3][4] Although, the capacity of the stores regulator to alter iron absorption is low relative to the erythroid regulator, its function is critical for normal iron homeostasis, as demonstrated from findings in hereditary haemochromatosis (HH). HH patients, the majority of whom (.90%) are homozygous for a single missense mutation (C282Y) in the HFE gene, absorb excessive amounts of iron from the diet relative to body iron stores, indicating that the set point for the stores regulator may be changed.…”

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confidence: 99%

Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis

Kelleher

Ryan²,

Barrett³

et al. 2004

Gut

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Background and aims: While upregulation of divalent metal transporter 1 (DMT1) and iron regulated gene 1 (IREG1) within duodenal enterocytes is reported in patients with hereditary haemochromatosis (HH), these findings are controversial. Furthermore, the effect of HFE, the gene mutated in HH, on expression of these molecules is unclear. This study examines duodenal expression of these three molecules in HH patients (prior to and following phlebotomy), in patients with iron deficiency (ID), and in controls. Methods: DMT1, IREG1, and HFE mRNA were measured in duodenal tissue of C282Y homozygous HH patients, in ID patients negative for the C282Y mutation with a serum ferritin concentration less than 20 mg/l, and in controls negative for C282Y and H63D mutations with normal iron indices, using real time polymerase chain reaction. Results: DMT1 and IREG1 mRNA levels were not significantly different in non-phlebotomised (untreated) HH patients compared with controls. DMT1 expression was significantly increased in HH patients who had undergone phlebotomy therapy (treated) and in patients with ID compared with controls. IREG1 was significantly increased in ID patients relative to controls, and while IREG1 expression was 1.8-fold greater in treated HH patients, this was not statistically significant. HFE mRNA expression was not significantly different in any of the groups investigated relative to controls.Conclusions: These findings demonstrate that untreated HH patients do not have increased duodenal DMT1 and IREG mRNA, but rather phlebotomy increases expression of these molecules, reflecting the effect of phlebotomy induced erythropoiesis. Finally, HFE appears to play a minor role in the regulation of iron absorption by the duodenal enterocyte.

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“…The association between enhanced MPO expression and increased levels of free iron is characteristic of many inflammatory disorders including cardiovascular diseases such atherosclerosis, pulmonary diseases such as cystic fibrosis, neurodegenerative diseases such as Alzheimer's disease as well as arthritis, diabetes, and has been found to be a risk factor for various cancers [28,29,31,[70][71][72][73][74][75]. As free iron accumulates, it disturbs body processes by replacing certain vital minerals such as zinc, copper, and manganese in many enzymes, depleting vitamins such as vitamin E and D, and may lead to chronic infection and inflammation [76].…”

Section: Discussionmentioning

confidence: 99%

“…However, under a number of pathological conditions such as inflammatory diseases, in which ROS production can become excessive, HOCl is capable of mediating tissue damage [19,27]. Interestingly, many inflammatory disorders such as ovarian cancer and atherosclerosis, in which MPO/HOCl have been known to be elevated, are also associated with significant free iron accumulation [28][29][30][31]. Recently, we have highlighted the potential link between elevated HOCl and hemoprotein heme destruction, and subsequent generation of free iron [21,32,33].…”

Section: Introductionmentioning

confidence: 99%