scholarly journals Olfactory ferric and ferrous iron absorption in iron-deficient rats

2012 ◽  
Vol 302 (12) ◽  
pp. L1280-L1286 ◽  
Author(s):  
V. M. Ruvin Kumara ◽  
Marianne Wessling-Resnick
Keyword(s):  
Nasal Cavity ◽  
Ferrous Iron ◽  
Iron Uptake ◽  
Ferric Iron ◽  
Iron Absorption ◽  
Iron Status ◽  
Occupational Exposures ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Iron Deficient

The absorption of metals from the nasal cavity to the blood and the brain initiates an important route of occupational exposures leading to health risks. Divalent metal transporter-1 (DMT1) plays a significant role in the absorption of intranasally instilled manganese, but whether iron uptake would be mediated by the same pathway is unknown. In iron-deficient rats, blood 59Fe levels after intranasal administration of the radioisotope in the ferrous form were significantly higher than those observed for iron-sufficient control rats. Similar results were obtained when ferric iron was instilled intranasally, and blood levels of 59Fe were even greater in the iron-deficient rats compared with the amount of ferrous iron absorbed. Experiments with Belgrade ( b/b) rats showed that DMT1 deficiency limited ferric iron uptake from the nasal cavity to the blood compared with +/b controls matched for iron deficiency. These results indicate that olfactory uptake of ferric iron by iron-deficient rats involves DMT1. Western blot experiments confirmed that DMT1 levels are significantly higher in iron-deficient rats compared with iron-sufficient controls in olfactory tissue. Thus the molecular mechanism of olfactory iron absorption is regulated by body iron status and involves DMT1.

Pharmacokinetics of pulmonary manganese absorption: evidence for increased susceptibility to manganese loading in iron-deficient rats

2005 ◽  
Vol 288 (5) ◽  
pp. L887-L893 ◽  
Author(s):  
Elizabeth Heilig ◽  
Ramon Molina ◽  
Thomas Donaghey ◽  
Joseph D. Brain ◽  
Marianne Wessling-Resnick
Keyword(s):  
Iron Deficiency ◽  
Iron Absorption ◽  
Iron Status ◽  
Mrna Levels ◽  
Blood Clearance ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Pulmonary Uptake ◽  
Iron Deficient ◽  
Metal Absorption

High levels of airborne manganese can be neurotoxic, yet little is known about absorption of this metal via the lungs. Intestinal manganese uptake is upregulated by iron deficiency and is thought to be mediated by divalent metal transporter 1 (DMT1), an iron-regulated factor known to play a role in dietary iron absorption. To better characterize metal absorption from the lungs to the blood and test whether iron deficiency may modify this process, the pharmacokinetics of pulmonary manganese and iron absorption by control and iron-deficient rats were compared. Levels of DMT1 expression in the lungs were determined to explore potential changes induced by iron deficiency that might alter metal absorption. The pharmacokinetic curves for intratracheally instilled54Mn and59Fe were significantly different, suggesting that pulmonary uptake of the two metals involves different mechanisms. Intratracheally instilled iron-deficient rats had significantly higher blood54Mn levels, whereas blood59Fe levels were significantly reduced compared with controls. The same trend was observed when radioisotopes were delivered by intravenous injection, indicating that iron-deficient rats have altered blood clearance of manganese. In situ analysis revealed the presence of DMT1 transcripts in airway epithelium; however, mRNA levels did not change in iron deficiency. Although lung DMT1 levels and metal absorption did not appear to be influenced by iron deficiency, the differences in blood clearance of instilled manganese identified by this study support the idea that iron status can influence the potential toxicity of this metal.

Relationship between intestinal iron-transporter expression, hepatic hepcidin levels and the control of iron absorption

2002 ◽  
Vol 30 (4) ◽  
pp. 724-726 ◽  
Author(s):  
G.J. Anderson ◽  
D. M. Frazer ◽  
S.J. Wilkins ◽  
E. M. Becker ◽  
K. N. Millard ◽  
...  
Keyword(s):  
Iron Transport ◽  
Iron Absorption ◽  
Negative Regulator ◽  
Deficient Diet ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Hepcidin Expression ◽  
Iron Deficient ◽  
Transport Molecules

Hepcidin is an anti-microbial peptide predicted to be involved in the regulation of intestinal iron absorption. We have examined the relationship between the expression of hepcidin in the liver and the expression of the iron-transport molecules divalent-metal transporter 1, duodenal cytochrome b, hephaestin and Ireg1 in the duodenum of rats switched from an iron-replete to an iron-deficient diet or treated to induce an acute phase response. In each case, elevated hepcidin expression correlated with reduced iron absorption and depressed levels of iron-transport molecules. These data are consistent with hepcidin playing a role as a negative regulator of intestinal iron absorption.

Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1

2010 ◽  
Vol 298 (3) ◽  
pp. C477-C485 ◽  
Author(s):  
Marco T. Núñez ◽  
Victoria Tapia ◽  
Alejandro Rojas ◽  
Pabla Aguirre ◽  
Francisco Gómez ◽  
...  
Keyword(s):  
Translational Regulation ◽  
Fluorescent Protein ◽  
Iron Absorption ◽  
Iron Status ◽  
Basolateral Membrane ◽  
Membrane Domains ◽  
Divalent Metal Transporter 1 ◽  
Intestinal Iron Absorption ◽  
Divalent Metal Transporter ◽  
Iron Supply

Intestinal iron absorption comprises the coordinated activity of the influx transporter divalent metal transporter 1 (DMT1) and the efflux transporter ferroportin (FPN). In this work, we studied the movement of DMT1 and FPN between cellular compartments as a function of iron supply. In rat duodenum, iron gavage resulted in the relocation of DMT1 to basal domains and the internalization of basolateral FPN. Considerable FPN was also found in apical domains. In Caco-2 cells, the apical-to-basal movement of cyan fluorescent protein-tagged DMT1 was complete 90 min after the addition of iron. Steady-state membrane localization studies in Caco-2 cells revealed that iron status determined the apical/basolateral membrane distribution of DMT1 and FPN. In agreement with the membrane distribution of the transporters,55Fe flux experiments revealed inward and outward iron fluxes at both membrane domains. Antisense oligonucleotides targeted to DMT1 or FPN inhibited basolateral iron uptake and apical iron efflux, respectively, indicating the participation of DMT1 and FPN in these fluxes. The fluxes were regulated by the iron supply; increased iron reduced apical uptake and basal efflux and increased basal uptake and apical efflux. These findings suggest a novel mechanism of regulation of intestinal iron absorption based on inward and outward fluxes at both membrane domains, and repositioning of DMT1 and FPN between membrane and intracellular compartments as a function of iron supply. This mechanism should be complementary to those based in the transcriptional or translational regulation of iron transport proteins.

Effect of DMT1 Mutations at Birth and in the First Years of Life.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3586-3586
Author(s):  
Iolascon Achille ◽  
d’Apolito Maria ◽  
Servedio Veronica ◽  
De Falco Luigia ◽  
Piga Antonio ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Uptake ◽  
Iron Absorption ◽  
Transferrin Saturation ◽  
Adult Life ◽  
Microcytic Anemia ◽  
Hepatic Iron ◽  
Liver Iron ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter

Abstract Divalent metal transporter 1 (DMT1) is involved in dietary iron uptake on the luminal side of duodenal enterocytes and transfers iron from the endosome to the cytosol in the marrow erythroblasts. Spontaneous (mk mice and Belgrade rats) or acquired (DMT1 -/- mice) inactivation of DMT1 in rodents produces a severe microcytic anemia at birth, caused by inefficient intestinal iron absorption and defective iron utilization in erythroid cells. The first reported patient with DMT1 mutations had microcytic anemia and iron overload in adult life. We here report the hematological phenotype of a newborn with a severe mycrocytic anemia (Hb 4 g/dL, MCV 71 fL) at birth and during the first months of life. Serum iron, transferrin saturation and serum ferritin were 160 microg/L, 100% and 846 ng/ml respectively at 3 months of age. Hepatic iron overload wad documented at the age of 5 years by both non invasive SQUID and liver biopsy. Sequence analysis of genomic DNA of the family revealed that the child was compound heterozygote for two novel DMT1 mutations, inherited by the asymptomatic parents. The first change deleted 3 bp (c.310 - 3_5del CTT) in intron 4 resulting in a splicing abnormality and the skipping of exon 5. The second was C>T 1246 substitution that causes arginine > cysteine replacement at position 416 (p. R416C) in the protein. This missense affects an highly conserved residue in one of the putative transmembrane domains. A striking reduction of the protein in peripheral blood cells of the proband was demonstrated by western blot using an anti-DMT1 antibody. The child required blood transfusions at birth and in the first two months of life. Thereafter, treatment with subcutaneous erythropoietin mantained hemoglobin levels between 7.5–9.5 g/dL, allowing transfusion-independence. The haematological phenotype of this patient highlights the essential role of DMT1 in erythropoiesis. The early and significant hepatic iron accumulation indicates that, as in animal models, DMT1 is dispensable for liver iron uptake. Finally DMT1 inactivation in the gut is likely bypassed by other pathways of iron absorption.

scholarly journals Interrelationships between circulating gastrin and iron status in mice and humans

2008 ◽  
Vol 295 (4) ◽  
pp. G855-G861 ◽  
Author(s):  
Suzana Kovac ◽  
Kelly Smith ◽  
Gregory J. Anderson ◽  
John R. Burgess ◽  
Arthur Shulkes ◽  
...  
Keyword(s):  
Iron Homeostasis ◽  
Iron Absorption ◽  
Iron Status ◽  
Transferrin Saturation ◽  
Wild Type ◽  
Liver Iron ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Mrna Concentration

The observations that the peptide hormone gastrin interacts with transferrin in vitro and that circulating gastrin concentrations are increased in the iron-loading disorder hemochromatosis suggest a possible link between gastrin and iron homeostasis. This study tested the hypothesis that gastrin and iron status are interrelated by measurement of iron homeostasis in mice and humans with abnormal circulating gastrin concentrations. Intestinal iron absorption was determined by59Fe uptake following oral gavage, and concentrations of duodenal divalent metal transporter-1 (DMT-1) and hepatic hepcidin mRNAs were determined by quantitative real-time PCR in agastrinemic (GasKO), hypergastrinemic cholecystokinin 2 receptor-deficient (CCK2RKO), or wild-type mice. Iron status was measured by standard methods in the same mice and in hypergastrinemic humans with multiple endocrine neoplasia type 1 (MEN-1). Iron absorption was increased sixfold and DMT-1 mRNA concentration fourfold, and transferrin saturation was reduced 0.8-fold and hepcidin mRNA expression 0.5-fold in juvenile GasKO mice compared with age-matched wild-type mice. In mature mice, few differences were observed between the strains. Juvenile CCK2RKO mice were hypergastrinemic and had a 5.4-fold higher DMT-1 mRNA concentration than wild-type mice without any increase in iron absorption. In contrast to juvenile GasKO mice, juvenile CCK2RKO mice had a 1.5-fold greater transferrin saturation, which was reflected in a twofold increase in liver iron deposition at maturity compared with wild-type mice. The correlation between transferrin saturation and circulating gastrin concentration observed in mutant mice was also observed in human patients with MEN, in whom hypergastrinemia correlated positively ( P = 0.004) with an increased transferrin saturation. Our data indicate that, in juvenile animals when iron demand is high, circulating gastrin concentrations may alter iron status by a CCK2R-independent mechanism.

Separate pathways for cellular uptake of ferric and ferrous iron

2000 ◽  
Vol 279 (4) ◽  
pp. G767-G774 ◽  
Author(s):  
Marcel E. Conrad ◽  
Jay N. Umbreit ◽  
Elizabeth G. Moore ◽  
Lucille N. Hainsworth ◽  
Michael Porubcin ◽  
...  
Keyword(s):  
Tissue Culture ◽  
Cellular Uptake ◽  
Ferrous Iron ◽  
Ferric Iron ◽  
Cultured Cells ◽  
Competitive Inhibition ◽  
Culture Media ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Iron And Manganese

Separate pathways for transport of nontransferrin ferric and ferrous iron into tissue cultured cells were demonstrated. Neither the ferric nor ferrous pathway was shared with either zinc or copper. Manganese shared the ferrous pathway but had no effect on cellular uptake of ferric iron. We postulate that ferric iron was transported into cells via β3-integrin and mobilferrin (IMP), whereas ferrous iron uptake was facilitated by divalent metal transporter-1 (DMT-1; Nramp-2). These conclusions were documented by competitive inhibition studies, utilization of a β3-integrin antibody that blocked uptake of ferric but not ferrous iron, development of an anti-DMT-1 antibody that blocked ferrous iron and manganese uptake but not ferric iron, transfection of DMT-1 DNA into tissue culture cells that showed enhanced uptake of ferrous iron and manganese but neither ferric iron nor zinc, hepatic metal concentrations in mk mice showing decreased iron and manganese but not zinc or copper, and data showing that the addition of reducing agents to tissue culture media altered iron binding to proteins of the IMP and DMT-1 pathways. Although these experiments show ferric and ferrous iron can enter cells via different pathways, they do not indicate which pathway is dominant in humans.

Effect of hepcidin on intestinal iron absorption in mice

Blood ◽  
2004 ◽  
Vol 103 (10) ◽  
pp. 3940-3944 ◽  
Author(s):  
Abas H. Laftah ◽  
Bala Ramesh ◽  
Robert J. Simpson ◽  
Nita Solanky ◽  
Seiamak Bahram ◽  
...  
Keyword(s):  
Iron Uptake ◽  
Iron Absorption ◽  
Iron Status ◽  
Hfe Gene ◽  
Chain Reaction ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Iron Deficient ◽  
Polymerase Chain

Abstract The effect of the putative iron regulatory peptide hepcidin on iron absorption was investigated in mice. Hepcidin peptide was synthesized and injected into mice for up to 3 days, and in vivo iron absorption was measured with tied-off segments of duodenum. Liver hepcidin expression was measured by reverse transcriptase–polymerase chain reaction. Hepcidin significantly reduced mucosal iron uptake and transfer to the carcass at doses of at least 10 μg/mouse per day, the reduction in transfer to the carcass being proportional to the reduction in iron uptake. Synthetic hepcidin injections down-regulated endogenous liver hepcidin expression excluding the possibility that synthetic hepcidin was functioning by a secondary induction of endogenous hepcidin. The effect of hepcidin was significant at least 24 hours after injection of hepcidin. Liver iron stores and hemoglobin levels were unaffected by hepcidin injection. Similar effects of hepcidin on iron absorption were seen in iron-deficient and Hfe knockout mice. Hepcidin inhibited the uptake step of duodenal iron absorption but did not affect the proportion of iron transferred to the circulation. The effect was independent of iron status of mice and did not require Hfe gene product. The data support a key role for hepcidin in the regulation of intestinal iron uptake.

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