Iron increases expression of iron-export protein MTP1 in lung cells

2002 ◽  
Vol 283 (5) ◽  
pp. L932-L939 ◽  
Author(s):  
Funmei Yang ◽  
Xinchao Wang ◽  
David J. Haile ◽  
Claude A. Piantadosi ◽  
Andrew J. Ghio
Keyword(s):  
Protein Level ◽  
Iron Homeostasis ◽  
Tissue Injury ◽  
Fold Increase ◽  
Lung Cells ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Lung Defense

Accumulation of reactive iron in acute and chronic lung disease suggests that iron-driven free radical formation could contribute to tissue injury. Safe transport and sequestration of this metal is likely to be of importance in lung defense. We provide evidence for the expression and iron-induced upregulation of the metal transporter protein-1 (MTP1) genes in human and rodent lung cells at both the protein and mRNA levels. In human bronchial epithelial cells, a 3.8-fold increase in mRNA level and a 2.4-fold increase in protein level of MTP1 were observed after iron exposure. In freshly isolated human macrophages, as much as an 18-fold increase in the MTP1 protein level was detected after incubation with an iron compound. The elevation in expression of MTP1 gene was also demonstrated in iron-instilled rat lungs and in hypotransferrinemic mouse lungs. This is similar to our previous findings with divalent metal transporter-1 (DMT1), an iron transporter that is required for iron uptake and intracellular iron trafficking. These studies suggest the presence of iron mobilization and/or detoxification pathways in the lung that are crucial for iron homeostasis and lung defense.

scholarly journals Manganese source affects manganese transport and gene expression of divalent metal transporter 1 in the small intestine of broilers

2011 ◽  
Vol 108 (2) ◽  
pp. 267-276 ◽  
Author(s):  
Shi-Ping Bai ◽  
Lin Lu ◽  
Rui-Lian Wang ◽  
Lin Xi ◽  
Li-Yang Zhang ◽  
...  
Keyword(s):  
Small Intestine ◽  
Control Diet ◽  
Divalent Metal ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Proximal Small Intestine ◽  
Hepatic Portal Vein ◽  
Hepatic Portal

In the present study, two experiments were conducted to investigate the effect of Mn source on Mn transport and the expression of a Mn transporter, divalent metal transporter 1 (DMT1), in the small intestine of broilers. In Expt 1, in situ ligated duodenal loops from Mn-deficient chicks (29-d-old) were perfused with solutions containing 0–8·74 mmol Mn/l from either MnSO4, or one of two organic chelates of Mn and amino acids with moderate (OM) or strong (OS) chelation strength (Qf) up to 30 min. In Expt 2, Mn-deficient intact broilers (14-d-old) were fed a control diet (12·45 mg Mn/kg) or the control diet supplemented with 100 mg Mn/kg as one of all Mn sources for 14 d. The uptake kinetics of Mn from different Mn sources in the ligated duodenal loops followed a saturable process as determined by regression analysis of concentration-dependent uptake rates. The maximum transport rate (Jmax) and Km values, and DMT1 mRNA levels in the ligated duodenal loops were higher (P < 0·01) for OM and OS than for MnSO4. DMT1 mRNA levels were much higher (P < 0·01) in the duodenum than in the jejunum and ileum. Both DMT1 mRNA levels in the duodenum and plasma Mn contents from the hepatic portal vein of intact chicks on day 14 post-feeding increased (P < 0·05) in the following order: control < MnSO4 < OM < OS. These results indicated that organic Mn sources with stronger Qf showed higher Mn transport and absorption, and DMT1 might be involved in the regulation of organic Mn transport in the proximal small intestine of broilers.

Nramp1 Promotes Efficient Macrophage Recycling of Iron Following Phenylhydrazine-Induced Hemolytic Anemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 415-415
Author(s):  
Shan Soe-Lin ◽  
Bill Andriopoulos ◽  
Marc Andrews ◽  
Matthias Schranzhofer ◽  
Tanya Kahawita ◽  
...  
Keyword(s):  
Hemolytic Anemia ◽  
Knockout Mice ◽  
Transferrin Saturation ◽  
Divalent Metal ◽  
Natural Resistance ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Hepcidin Mrna

Abstract Natural resistance-associated macrophage protein 1 (Nramp1) is a divalent metal transporter expressed exclusively in phagocytic cells such as macrophages and neutrophils. Based on our earlier in vitro study (Soe-Lin et al. Exp Hematol.2008;36:929–937), we hypothesize that Nramp1 may participate in the recycling of iron acquired through the phagocytosis of senescent red blood cells by macrophages. In order to examine the effect of Nramp1 on iron recycling in vivo, the iron parameters of wildtype (Nramp1+/+) and Nramp1 knockout mice (Nramp1−/−) were analyzed following both acute and chronic induction of hemolytic anemia by phenylhydrazine treatment. We observe that untreated Nramp1−/− mice exhibited greater serum transferrin saturation and splenic iron content, higher duodenal ferroportin (Fpn) and divalent metal transporter 1 (DMT1) expression, and dramatically lower hepcidin mRNA levels than untreated Nramp1+/+ mice. Significant iron loading of the reticuloendothelial organs was found to increase with age in knockout mice. Following acute treatment with the hemolytic agent phenylhydrazine, Nramp1−/− mice experienced a significant decrease in serum iron levels and hematocrit, while their Nramp1+/+ counterparts were relatively unaffected. Following a month-long phenylhydrazine regimen, Nramp1−/− mice retained markedly increased quantities of iron within the liver and spleen, and exhibited greater splenomegaly and reticulocytosis than wild-type mice. Furthermore, while hepcidin mRNA levels decreased following chronic phenylhydrazine treatment in both Nramp1+/+ and Nramp1−/− mice, this effect was significantly more pronounced in Nramp1−/− mice. The data presented in this report suggest that in the absence of Nramp1, iron accumulates to a greater degree within reticuloendothelial organs such as the liver and spleen following acute and chronic hemolytic anemia. We hypothesize that the low hepcidin mRNA levels seen in Nramp1−/− mice are a response to a diminished availability of iron for erythropoiesis resulting from the aberrant increase in iron retention within their splenic reticuloendothelial macrophages. Our observation of increased DMT1 and ferroportin within the duodenums of the Nramp1−/− animals imply that the increase in transferrin saturation despite the impaired iron release from erythrophagocytosing macrophages occurs due to a compensatory increase in iron absorption from the diet. These findings are consistent with our hypothesis that Nramp1 promotes the efficient recycling of iron in erythrophagocytosing macrophages.

Deregulation of proteins involved in iron metabolism in hepcidin-deficient mice

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4861-4864 ◽  
Author(s):  
Lydie Viatte ◽  
Jeanne-Claire Lesbordes-Brion ◽  
Dan-Qing Lou ◽  
Myriam Bennoun ◽  
Gaël Nicolas ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Homeostasis ◽  
Genetic Disorder ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
The Common ◽  
Related Proteins ◽  
Deficient Mice

Abstract Evidence is accumulating that hepcidin, a liver regulatory peptide, could be the common pathogenetic denominator of all forms of iron overload syndromes including HFE-related hemochromatosis, the most prevalent genetic disorder characterized by inappropriate iron absorption. To understand the mechanisms whereby hepcidin controls iron homeostasis in vivo, we have analyzed the level of iron-related proteins by Western blot and immunohistochemistry in hepcidin-deficient mice, a mouse model of severe hemochromatosis. These mice showed important increased levels of duodenal cytochrome b (Dcytb), divalent metal transporter 1 (DMT1), and ferroportin compared with control mice. Interestingly, the level of ferroportin was coordinately up-regulated in the duodenum, the spleen, and the liver (predominantly in the Kupffer cells). Finally, we also evidenced a decrease of ceruloplasmin in the liver of hepcidin-deficient mice. We hypothesized that the deregulation of these proteins might be central in the pathogenesis of iron overload, providing key therapeutic targets for iron disorders. (Blood. 2005;105:4861-4864)

scholarly journals Skeletal Lipocalin-2 Is Associated with Iron-Related Oxidative Stress in ob/ob Mice with Sarcopenia

Antioxidants ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 758
Author(s):  
Eun Bee Choi ◽  
Jae Hun Jeong ◽  
Hye Min Jang ◽  
Yu Jeong Ahn ◽  
Kyu Hyeon Kim ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Skeletal Muscle ◽  
Iron Homeostasis ◽  
Skeletal Muscle Regeneration ◽  
Lipocalin 2 ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Candidate Target ◽  
And Oxidative Stress

Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.

scholarly journals Influence of cytokines on Dmt1 iron transporter and ferritin expression in insulin-secreting cells

2014 ◽  
Vol 52 (3) ◽  
pp. 301-310 ◽  
Author(s):  
S Lortz ◽  
S Schröter ◽  
V Stückemann ◽  
I Mehmeti ◽  
S Lenzen
Keyword(s):  
Inflammatory Cytokines ◽  
Hydroxyl Radicals ◽  
Fold Increase ◽  
Divalent Metal Transporter 1 ◽  
Iron Storage ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Inflammatory Conditions ◽  
Insulin Producing Cells ◽  
Pro Inflammatory Cytokines

Free intracellular ferrous iron (Fe2+) is essential for the generation of the extremely toxic hydroxyl radicals, which contribute to β-cell destruction by cytokines. Therefore the expression of the different divalent metal transporter 1 (Dmt1) isoforms and ferritin (Ft) subunits, responsible for iron import and chelation, was analyzed under pro-inflammatory conditions (IL1β alone or together with TNFα+IFNγ). The Dmt1 isoforms (1A/1B and +IRE/−IRE) and the totalDmt1expression in insulin-producing cells (RINm5F and INS-1E), in primary rat islets and, for comparison, in the neuroendocrine PC12 cell line were quantified by qRT-PCR. In addition, the expression of the light (L-Ft) and heavyFt(H-Ft) subunits and the mitochondrialFtisoform (Mtft) in insulin-producing cells under control conditions and after cytokine treatment was estimated. The 1B isoform was the predominantDmt1mRNA in all insulin-producing cells, accounting for almost 100% of the 1A/1B isoform expression. For the IRE variants, +IRE expression was higher than −IRE expression. Pro-inflammatory cytokines accelerated the expression ofDmt1isoforms significantly with an overall 2.5- to 3-fold increase in the totalDmt1expression. In contrast, the expression of the iron-buffering ferritin subunits L- and H-Ftwas unaffected by IL1β and only slightly induced by the cytokine mixture.Mtftexpression was also not increased.Dmt1expression was significantly elevated through pro-inflammatory cytokines, whereasFtexpression was marginally increased. This imbalance between the increased iron transport capacity and the almost unaffected iron storage capacity can foster cytokine-mediated formation of hydroxyl radicals and thus pro-inflammatory cytokine toxicity through elevated free iron concentrations.

Cytokine-mediated regulation of iron transport in human monocytic cells

Blood ◽  
2003 ◽  
Vol 101 (10) ◽  
pp. 4148-4154 ◽  
Author(s):  
Susanne Ludwiczek ◽  
Elmar Aigner ◽  
Igor Theurl ◽  
Günter Weiss
Keyword(s):  
Iron Uptake ◽  
Iron Transport ◽  
Divalent Metal ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Regulatory Pathways ◽  
Metal Transporter ◽  
Cellular Expression ◽  
Ifn Γ

Abstract Under chronic inflammatory conditions cytokines induce a diversion of iron traffic, leading to hypoferremia and retention of the metal within the reticuloendothelial system. However, the regulatory pathways underlying these disturbances of iron homeostasis are poorly understood. We investigated transferrin receptor (TfR)–dependent and –independent iron transport mechanisms in cytokine-stimulated human monocytic cell lines THP-1 and U937. Combined treatment of cells with interferon-γ (IFN-γ) and lipopolysaccharide (LPS) reduced TfR mRNA levels, surface expression, and iron uptake, and these effects were reversed by interleukin-10 (IL-10), thus stimulating TfR-mediated iron acquisition. IFN-γ and LPS dose-dependently increased the cellular expression of divalent metal transporter-1, a transmembrane transporter of ferrous iron, and stimulated the uptake of nontransferrin bound iron (NTBI) into cells. At the same time, IFN-γ and LPS down-regulated the expression of ferroportin mRNA, a putative iron exporter, and decreased iron release from monocytes. Preincubation with IL-10 partly counteracted these effects. Our results demonstrate that the proinflammatory stimuli IFN-γ and LPS increase the uptake of NTBI via stimulation of divalent metal transporter-1 expression and cause retention of the metal within monocytes by down-regulating ferroportin synthesis. Opposite, the anti-inflammatory cytokine IL-10 stimulates TfR-mediated iron uptake into activated monocytes. The regulation of iron transport by cytokines is a key mechanism in the pathogenesis of anemia of chronic disease and a promising target for therapeutic intervention.

Role of the kidney in iron homeostasis: renal expression of Prohepcidin, Ferroportin, and DMT1 in anemic mice

2008 ◽  
Vol 295 (4) ◽  
pp. F1213-F1221 ◽  
Author(s):  
Tania Veuthey ◽  
María Cecilia D'Anna ◽  
Marta Elena Roque
Keyword(s):  
Hemolytic Anemia ◽  
Iron Homeostasis ◽  
Renal Medulla ◽  
Renal Tissue ◽  
Proximal Tubules ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Tissue Iron ◽  
Renal Expression

It is known that renal tissue plays a role in normal iron homeostasis. The current study examines kidney function in iron metabolism under hemolytic anemia studying renal expression of Prohepcidin, Ferroportin (MTP1), and divalent metal transporter 1 (DMT1). The relationship between these proteins and iron pigments was also investigated. Immunohistochemical procedures to study renal expression of Prohepcidin, MTP1, and DMT1 were performed in healthy and anemic mice. Renal tissue iron was determined by Prussian blue iron staining. To assess anemia evolution and erythropoietic recovery, we used conventional tests. In healthy mice, Prohepcidin expression was marked in proximal tubules and inner medulla and absent in outer medulla. Cortical tissue of healthy mice also showed MTP1 immunostaining, mainly in the S2 segment of proximal tubules. Medullar tissue showed MTP1 expression in the inner zone. In addition, S2 segments showed intense DMT1 immunoreactivity with homogeneous DMT1 distribution throughout renal medulla. The main cortical findings in hemolytic anemia were in S2 segments of proximal tubules where we found that decreased Prohepcidin expression coincided with an increment in Ferroportin and DMT1 expression. This expression pattern was concomitant with increased iron in the same tubular zone. However, in medullar tissue both Prohepcidin and MTP1 decreased and DMT1 was detected mainly in larger diameter tubules. Our findings clearly demonstrate that in hemolytic anemia, renal Prohepcidin acts in coordination with renal Ferroportin and DMT1, indicating the key involvement of kidney in iron homeostasis when iron demand is high. Further research is required to learn more about these regulatory mechanisms.

scholarly journals Dietary inulin affects the expression of intestinal enterocyte iron transporters, receptors and storage protein and alters the microbiota in the pig intestine

2008 ◽  
Vol 99 (3) ◽  
pp. 472-480 ◽  
Author(s):  
E. Tako ◽  
R. P. Glahn ◽  
R. M. Welch ◽  
X. Lei ◽  
K. Yasuda ◽  
...  
Keyword(s):  
Control Group ◽  
Mrna Levels ◽  
Divalent Metal Transporter 1 ◽  
Mineral Absorption ◽  
Bacterial Dna ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Genes Encoding ◽  
Diet Control ◽  
And Storage

Inulin, a linear β fructan, is present in a variety of plants including chicory root and wheat. It exhibits prebiotic properties and has been shown to enhance mineral absorption and increase beneficial bacteria in the colon. The aim of the present study was to assess the effect of dietary inulin on the gene expression of selected intestinal Fe transporters and binding proteins. Anaemic piglets at age 5 weeks were allocated to a standard maize–soya diet (control) or the same diet supplemented with inulin at a level of 4 %. After 6 weeks, the animals were killed and caecum contents and sections of the duodenum and colon were removed. Segments of the genes encoding for the pig divalent metal transporter 1 (DMT1) and duodenal cytochrome-b reductase (Dcytb) were isolated and sequenced. Semi-quantitative RT-PCR analyses were performed to evaluate the expression of DMT1, Dcytb, ferroportin, ferritin, transferrin receptor (TfR) and mucin genes. DMT1, Dcytb, ferroportin, ferritin and TfR mRNA levels in duodenal samples were significantly higher in the inulin group (P ≤ 0·05) compared with the control. In colon, DMT1, TfR and ferritin mRNA levels significantly increased in the inulin group. Additionally, the caecal content microflora was examined using 16S rDNA targeted probes from bacterial DNA. TheLactobacillusandBifidobacteriumpopulations were significantly increased in the inulin group (P ≤ 0·05) compared with the control group. These results indicate that dietary inulin might trigger an up regulation of genes encoding for Fe transporters in the enterocyte. The specific mechanism for this effect remains to be elucidated.

scholarly journals Intestinal ferritinophagy is regulated by HIF-2α and is essential for systemic iron homeostasis

2020 ◽  
Author(s):  
Nupur K Das ◽  
Amanda Sankar ◽  
Andrew J Schwartz ◽  
Sumeet Solanki ◽  
Xiaoya Ma ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Whole Body ◽  
Null Mouse ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Iron Sequestration

AbstractIron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2α regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2α. Duodenal NCOA4 expression is regulated by HIF-2α during high systemic iron demands. Moreover, overexpression of intestinal HIF-2α is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2α target. To demonstrate the importance of intestinal HIF-2α/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

Lung injury after ozone exposure is iron dependent

2007 ◽  
Vol 292 (1) ◽  
pp. L134-L143 ◽  
Author(s):  
Andrew J. Ghio ◽  
Jennifer L. Turi ◽  
Michael C. Madden ◽  
Lisa A. Dailey ◽  
Judy D. Richards ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lung Injury ◽  
Iron Homeostasis ◽  
Biological Effects ◽  
Ozone Exposure ◽  
Divalent Metal Transporter 1 ◽  
Hek 293 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Elevated Expression

We tested the hypothesis that oxidative stress and biological effect after ozone (O3) exposure are dependent on changes in iron homeostasis. After O3 exposure, healthy volunteers demonstrated increased lavage concentrations of iron, transferrin, lactoferrin, and ferritin. In normal rats, alterations of iron metabolism after O3 exposure were immediate and preceded the inflammatory influx. To test for participation of this disruption in iron homeostasis in lung injury following O3 inhalation, we exposed Belgrade rats, which are functionally deficient in divalent metal transporter 1 (DMT1) as a means of iron uptake, and controls to O3. Iron homeostasis was disrupted to a greater extent and the extent of injury was greater in Belgrade rats than in control rats. Nonheme iron and ferritin concentrations were higher in human bronchial epithelial (HBE) cells exposed to O3 than in HBE cells exposed to filtered air. Aldehyde generation and IL-8 release by the HBE cells was also elevated following O3 exposure. Human embryonic kidney (HEK 293) cells with elevated expression of a DMT1 construct were exposed to filtered air and O3. With exposure to O3, elevated DMT1 expression diminished oxidative stress (i.e., aldehyde generation) and IL-8 release. We conclude that iron participates critically in the oxidative stress and biological effects after O3 exposure.

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