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Concept: DMT1

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The relation between Lead (Pb) and iron (Fe) becomes increasingly concerned because they are both divalent metals that are absorbed by the same intestinal mechanism, and Pb exposure and Fe deficiency in the developmental brain, as well as Fe overload in the aged brain, can cause cognitive deficits. However, the interaction between Pb exposure and Fe status in the brain has not been established. Therefore, in the current study, we examined the effects of maternal ingestion of Pb in drinking water during gestation and lactation on the Fe status and the expression of divalent metal transporter 1 (DMT1) and ferroportin 1 (FP1) in the brain of offspring. The offspring were followed through old age, with measurements taken at postnatal week 3, 41 and 70. Pb exposure increases the Fe content in the old-aged rats' brain, Which might be not subjected to DMT1 mediating, but may be associated with the decrease expression of FP1. Furthermore, the effect of Pb on FP1 expression is regulated at transcriptional and posttranscriptional levels. The perturbation in Fe homeostasis may contribute to the neurotoxicology consequences induced by Pb exposure, and FP1 may play a role in Pb-induced Fe cumulation in the brain.

Concepts: Iron, Metal, Old age, Human iron metabolism, Lead poisoning, DMT1, Ferroportin, Hepcidin

2

Iron and copper are essential trace metals, actively absorbed from the proximal gut in a regulated fashion. Depletion of either metal can lead to anemia. In the gut, copper deficiency can affect iron absorption through modulating the activity of hephaestin - a multi-copper oxidase required for optimal iron export from enterocytes. How systemic copper status regulates iron absorption is unknown. Mice were subjected to a nutritional copper deficiency-induced anemia regime from birth and injected with copper sulphate intraperitoneally to correct the anemia. Copper deficiency resulted in anemia, increased duodenal hypoxia and Hypoxia inducible factor 2α (HIF-2α) levels, a regulator of iron absorption. HIF-2α upregulation in copper deficiency appeared to be independent of duodenal iron or copper levels and correlated with the expression of iron transporters (Ferroportin - Fpn, Divalent Metal transporter - Dmt1) and ferric reductase - Dcytb. Alleviation of copper-dependent anemia with intraperitoneal copper injection resulted in down regulation of HIF-2α-regulated iron absorption genes in the gut. Our work identifies HIF-2α as an important regulator of iron transport machinery in copper deficiency.

Concepts: Iron, Liver, Metal, Copper, Sulfuric acid, Digestion, Human iron metabolism, DMT1

1

The amount of iron in the diet directly influences the composition of the microbiota. Inversely, the effects of the microbiota on iron homeostasis have been little studied. So, we investigate whether the microbiota itself may alter host iron sensing. Duodenal cytochrome b and divalent metal transporter 1, involved in apical iron uptake, are 8- and 10-fold, respectively, more abundant in the duodenum of germ-free (GF) mice than in mice colonized with a microbiota. In contrast, the luminal exporter ferroportin is 2-fold less abundant in GF. The overall signature of microbiota on iron-related proteins is similar in the colon. The colonization does not modify systemic parameters as plasma transferrin saturation (20%), plasma ferritin (150 ng/L), and liver (85 µg/g) iron load. Commensal organisms (Bacteroides thetaiotaomicron VPI-5482 and Faecalibacterium prausnitzii A2-165) and a probiotic strain (Streptococcus thermophilus LMD-9) led to up to 12-fold induction of ferritin in colon. Our data suggest that the intestinal cells of GF mice are depleted of iron and that following colonization, the epithelial cells favor iron storage. This study is the first to demonstrate that gut microbes induce a specific iron-related protein signature, highlighting new aspects of the crosstalk between the microbiota and the intestinal epithelium.-Deschemin, J.-C., Noordine, M.-L., Remot, A., Willemetz, A., Afif, C., Canonne-Hergaux, F., Langella, P., Karim, Z., Vaulont, S., Thomas, M., Nicolas, G. The microbiota shifts the iron sensing of intestinal cells.

Concepts: Protein, Gene, Bacteria, Gut flora, Iron, Human iron metabolism, Streptococcus thermophilus, DMT1

0

Many critical metabolic functions in the brain require adequate and timely delivery of iron. However, most studies when considering brain iron uptake have ignored the iron requirements of the endothelial cells that form the blood-brain barrier (BBB). Moreover, current models of BBB iron transport do not address regional regulation of brain iron uptake or how neurons, when adapting to metabolic demands, can acquire more iron. In this study, we demonstrate that both iron-poor transferrin (apo-Tf) and the iron chelator, deferoxamine, stimulate release of iron from iron-loaded endothelial cells in an in vitro BBB model. The role of the endosomal divalent metal transporter 1 (DMT1) in BBB iron acquisition and transport has been questioned. Here, we show that inhibition of DMT1 alters the transport of iron and Tf across the endothelial cells. These data support an endosome-mediated model of Tf-bound iron uptake into the brain and identifies mechanisms for local regional regulation of brain iron uptake. Moreover, our data provide an explanation for the disparity in the ratio of Tf to iron transport into the brain that has confounded the field.

Concepts: Neuron, Brain, Iron, Human brain, Ratio, Cerebrospinal fluid, Human iron metabolism, DMT1

0

Hypoxia-inducible factors (HIFs) are central mediators of cellular adaption to hypoxia. The heterodimeric HIF transcription factors consist of HIF-α and HIF-β, that form functional HIFs. Mammals contain HIF-1α, HIF-2α, and HIF-3α. HIFs play a key role in iron metabolism by regulating the expression of iron-related proteins, such as divalent metal transporter 1 (DMT1), ferroportin 1 (FPN1), duodenal cytochrome b (Dcytb), and transferrin receptor (TfR). Hepcidin and iron regulatory proteins (IRPs), the central mediators for systematic and intracellular iron homeostasis, are also regulated by HIFs. In this review, we summarized the regulatory effects of HIFs on iron-related proteins, thus providing insights into the control of HIFs as therapeutic strategies for some iron related disorders.

Concepts: Protein, Iron, Regulation, Human iron metabolism, Iron metabolism, DMT1, Ferroportin, Hepcidin

0

Iron deficiency anemia in celiac disease is related to impaired duodenal mucosal uptake, due to villous atrophy. Iron enters the enterocytes through an apical divalent metal transporter, DMT1. Different DMT1 transcripts have been identified, depending on the presence of an iron-responsive element that allows DMT1 up-regulation during iron starvation. An intronic DMT1 polymorphism, IVS4+44C>A, has been associated with metal toxicity, and the CC-carriers show high iron levels.

Concepts: Hemoglobin, Iron, Iron deficiency anemia, Malnutrition, Coeliac disease, Transferrin, Human iron metabolism, DMT1

0

Dietary non-heme ferric iron is reduced by the ferric reductase enzyme, duodenal cytochrome b (Dcytb), before absorption by the divalent metal transporter 1 (DMT1). A single nucleotide polymorphism (SNP rs10455 mutant) that is located in the last exon of the Dcytb gene was reported in C282Y haemochromatosis HFE subjects. The present work therefore investigated the phenotype of this mutant Dcytb in Chinese hamster ovary (CHO) cells. These cultured cells were transfected with either wild type (WT) or the SNP vector plasmids of Dcytb. Ferric reductase assays were performed in Dcytb transgenic CHO cells using the ferrozine spectrophometric assay protocol. The Dcytb SNP rs10455 showed a gain-of-function capability since ferric reductase activity increased significantly (p < 0.01) in the transgenic cells. Varying ferric reductase activity was found when CHO cells were pretreated with modulators of Dcytb protein expression. Although ferric reductase in endogenous CHO cells increased with deferoxamine or CoCl2, iron loading with ferric ammonium citrate (FAC) had the opposite effect. Taken together, the study reveals a gain-of-function phenotype for Dcytb rs10455 mutation that could be a putative modifier of colorectal cancer risk, with attendant variability in penetrance among human HFE C282Y homozygotes.

Concepts: DNA, Protein, Gene, Molecular biology, Iron, Cell culture, Chinese hamster, DMT1

0

This study compares the absorption characteristics of two iron-based dietary supplements and their biocompatibility to bisglycinate iron, a common chelated iron form. The Caco-2 cell line-a model of human intestinal absorption-and GTL-16 cell line-a model of gastric epithelial cells-were used to perform the experiments; in the first experiments, the kinetics of absorption have been evaluated analyzing the divalent metal transporter 1 (DMT1) expression. Three different iron combinations containing 50 µM iron (named Fisioeme(®), Sideral(®) and bisglycinate) were used for different stimulation times (1-24 h). After this, the effects of the three iron formulations were assessed in both a short and a long time, in order to understand the extrusion mechanisms. The effects of the three different formulations were also analyzed at the end of stimulation period immediately after iron removal, and after some time in order to clarify whether the mechanisms were irreversibly activated. Findings obtained in this study demonstrate that Fisioeme(®) was able to maintain a significant beneficial effect on cell viability compared to control, to Sideral(®), and to iron bisglycinate. This observation indicates that Fisioeme(®) formulation is the most suitable for gastric and intestinal epithelial cells.

Concepts: Human, Digestive system, Epithelium, Stomach, Small intestine, Digestion, Intestinal epithelium, DMT1

0

In humans, the H(+)-coupled Fe(2+) transporter DMT1 (SLC11A2) is essential for proper maintenance of iron homeostasis. While X-ray diffraction has recently unveiled the structure of the bacterial homologue ScaDMT as a LeuT-fold transporter, the exact mechanism of H(+)-cotransport has remained elusive. Here, we used a combination of molecular dynamics simulations, in silico pK a calculations and site-directed mutagenesis, followed by rigorous functional analysis, to discover two previously uncharacterized functionally relevant residues in hDMT1 that contribute to H(+)-coupling. E193 plays a central role in proton binding, thereby affecting transport properties and electrogenicity, while N472 likely coordinates the metal ion, securing an optimally “closed” state of the protein. Our molecular dynamics simulations provide insight into how H(+)-translocation through E193 is allosterically linked to intracellular gating, establishing a novel transport mechanism distinct from that of other H(+)-coupled transporters.

Concepts: Electron, Oxygen, Iron, Hydrogen, Atom, Transport, Human iron metabolism, DMT1

0

The interaction among heart failure (HF), chronic kidney disease (CKD), and anemia is called cardio-renal anemia syndrome. The mechanism of anemia in cardio-renal anemia syndrome is complex and remains completely unknown. We have previously reported that impaired intestinal iron transporters may contribute to the mechanism of anemia in HF using in vivo HF model rats. In this study, we assessed intestinal iron transporters in CKD model rats to investigate the association of intestinal iron transporters in the mechanism of cardio-renal anemia syndrome. CKD was induced by 5/6 nephrectomy in Sprague-Dawley rats. Sham-operated rats served as a control. After 24-week surgery, CKD rats exhibited normocytic normochromic anemia and normal serum erythropoietin levels despite of anemia. Serum iron levels were decreased in CKD rats compared with the controls. Of interest, intestinal expression of critical iron importers, such as duodenal cytochrome b (Dcyt-b) and divalent metal transporter 1 (DMT-1), was decreased in CKD rats compared with the controls. On the other hand, intestinal expression of ferroportin, an intestinal iron exporter, was not different in the control and CKD groups. Moreover, hepatic expression of hepcidin, a regulator of iron homeostasis, did not differ between the control and CKD groups. These results suggest that impaired intestinal expression of Dcyt-b and DMT-1 might be associated with the reduction of an iron uptake in CKD. Taken together, impaired these intestinal iron transporters may become a novel therapeutic target for cardio-renal anemia syndrome.

Concepts: Chronic kidney disease, Kidney, Erythropoietin, Iron, Anemia, Iron deficiency anemia, Human iron metabolism, DMT1