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.

Iron Imports. V. Transport of iron through the intestinal epithelium

2006 ◽  
Vol 290 (3) ◽  
pp. G417-G422 ◽  
Author(s):  
Yuxiang Ma ◽  
Mary Yeh ◽  
Kwo-yih Yeh ◽  
Jonathan Glass
Keyword(s):  
Iron Transport ◽  
Brush Border Membrane ◽  
Iron Absorption ◽  
Basolateral Membrane ◽  
Apical Surface ◽  
Intracellular Iron ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Metal Transporter ◽  
Apical Compartment

Iron absorption across the brush-border membrane requires divalent metal transporter 1 (DMT1), whereas ferroportin (FPN) and hephaestin are required for exit across the basolateral membrane. However, how iron passes across the enterocyte is poorly understood. Both chaperones and transcytosis have been postulated to account for intracellular iron transport. With iron feeding, DMT1 undergoes endocytosis and FPN translocates from the apical cytosol to the basolateral membrane. The fluorescent metallosensor calcein offered to the basolateral surface of enterocytes is found in endosomes in the apical compartment, and its fluorescence is quenched when iron is offered to the apical surface. These experiments are consistent with vesicular iron transport as a possible pathway for intracellular iron transport.

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.

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.

Defective iron uptake by the duodenum of Belgrade rats fed diets of different iron contents

1996 ◽  
Vol 270 (5) ◽  
pp. G826-G832 ◽  
Author(s):  
P. S. Oates ◽  
E. H. Morgan
Keyword(s):  
Iron Content ◽  
Iron Uptake ◽  
Iron Transport ◽  
Iron Absorption ◽  
Microcytic Anemia ◽  
Deficient Diet ◽  
Hypochromic Microcytic Anemia ◽  
Iron Deficient

Homozygous Belgrade rats have an inherited hypochromic, microcytic anemia that is due to impaired iron transport into immature erythrocytes. There is also evidence for abnormal iron transport in other tissues such as the intestine. This study was aimed at investigating the intestinal defect in rats that had been fed diets for 12 days that are normal, low, or high in iron. The duodenal uptake, transfer, and absorption of Fe(III)-nitrilotriacetate and Fe(II)-ascorbate were studied using in vivo tied-off gut sacs in genetically normal rats and in heterozygous or homozygous Belgrade rats. In normal and heterozygous Belgrade rats, the handling of Fe(III) and Fe(II) was similar; uptake, transfer, and absorption of Fe(III) and Fe(II) changed inversely with the iron content of the diet. In contrast, in homozygous Belgrade rats the uptake of both Fe(III) and Fe(II) was markedly reduced and absorption of Fe(III) did not change when animals were fed an iron-deficient diet. Since absorption of Fe(II) was similar to Fe(III), there is no evidence that the defect in iron absorption is due to failure of a mechanism for reduction of Fe(III). The lowered uptake of Fe(III) and Fe(II) in homozygous Belgrade rats probably involves a defective iron carrier associated with the microvillous membrane of the duodenum.

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.

scholarly journals Matriptase-2 and Hemojuvelin in Hepcidin Regulation: In Vivo Immunoblot Studies in Mask Mice

2021 ◽  
Vol 22 (5) ◽  
pp. 2650
Author(s):  
Jan Krijt ◽  
Jana Frýdlová ◽  
Iuliia Gurieva ◽  
Petr Přikryl ◽  
Martin Báječný ◽  
...  
Keyword(s):  
Proteolytic Activity ◽  
Negative Regulator ◽  
Spleen Weight ◽  
Deficient Diet ◽  
Liver Iron ◽  
Hepcidin Expression ◽  
Stress Erythropoiesis ◽  
Iron Deficient

Matriptase-2, a serine protease expressed in hepatocytes, is a negative regulator of hepcidin expression. The purpose of the study was to investigate the interaction of matriptase-2 with hemojuvelin protein in vivo. Mice lacking the matriptase-2 proteolytic activity (mask mice) display decreased content of hemojuvelin protein. Vice versa, the absence of hemojuvelin results in decreased liver content of matriptase-2, indicating that the two proteins interact. To further characterize the role of matriptase-2, we investigated iron metabolism in mask mice fed experimental diets. Administration of iron-enriched diet increased liver iron stores as well as hepcidin expression. Treatment of iron-overloaded mask mice with erythropoietin increased hemoglobin and hematocrit, indicating that the response to erythropoietin is intact in mask mice. Feeding of an iron-deficient diet to mask mice significantly increased spleen weight as well as the splenic content of erythroferrone and transferrin receptor proteins, indicating stress erythropoiesis. Liver hepcidin expression was decreased; expression of Id1 was not changed. Overall, the results suggest a complex interaction between matriptase-2 and hemojuvelin, and demonstrate that hepcidin can to some extent be regulated even in the absence of matriptase-2 proteolytic activity.

Does Hepatic Hepcidin Play an Important Role in Exercise-Associated Anemia in Rats?

2011 ◽  
Vol 21 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Yu-Qian Liu ◽  
Yan-Zhong Chang ◽  
Bin Zhao ◽  
Hai-Tao Wang ◽  
Xiang-Lin Duan
Keyword(s):  
Regulatory Mechanism ◽  
Iron Absorption ◽  
White Blood Cells ◽  
Strenuous Exercise ◽  
Enzyme Linked Immunosorbent Assay ◽  
Control Group ◽  
Transcriptional Level ◽  
Divalent Metal Transporter 1 ◽  
Divalent Metal Transporter ◽  
Sports Anemia

Some athletes are diagnosed as suffering from sports anemia because of iron deficiency, but the regulatory mechanism remains poorly understood. It is reported that hepcidin may provide a way to illuminate the regulatory mechanism of exercise-associated anemia. Here the authors investigate the hepcidin-involved iron absorption in exercise-associated anemia. Twelve male Wistar rats (300 ± 10 g) were randomly divided into 2 groups, 6 in a control group (CG) and 6 in an exercise group (EG, 5 wk treadmill exercise of different intensities with progressive loading). Serum samples were analyzed for circulating levels of IL-6 by means of enzyme-linked immunosorbent assay (ELISA). The expression of hepatic hepcidin mRNA was examined by real-time polymerase chain reaction analysis. The protein levels of divalent metal transporter 1 (DMT1), ferroportin1 (FPN1), and heme-carrier protein 1 (HCP1) of duodenum epithelium were examined by Western blot. The results showed that the amount of iron and ferritin in serum were lower in EG than in CG (p < .05). The levels of IL-6 and white blood cells were greater in EG than in CG (p < .01). The expression of DMT1, HCP1, and FPN1 was significantly lower in EG than in CG (p < .01). The mRNA expressions of hepatic hepcidin and hemojuvelin in skeletal muscle were remarkably higher in EG than in CG. The data indicated that inflammation was induced by strenuous exercise, and as a result, the transcriptional level of the hepatic hepcidin gene was increased, which further inhibited the expression of iron-absorption proteins and led to exercise-associated anemia.

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