Ferrit(in)ing out new mechanisms in iron homeostasis.

Andrews NC.

Source

Departments of Pediatrics and Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. [email protected]

Abstract

Exquisite control of intestinal iron absorption prevents iron deficiency and toxic iron overload. Absorption is modulated by a circulating hormone, hepcidin, which inactivates the iron transporter ferroportin. In this issue of Cell Metabolism, Vanoaica and colleagues show that absorption is also regulated within the intestinal epithelium, through production of the iron-sequestering protein H-ferritin.

2010 Elsevier Inc. All rights reserved.

http://www.ncbi.nlm.nih.gov/pubmed?term=Cell%20Metab.%202010%20Sep%208%3B12(3)%3A203-4.%20Ferrit(in)ing%20out%20new%20mechanisms%20in%20iron%20homeostasis.%20Andrews%20NC.%20

Mol Cell. 2000 Feb;5(2):299-309.

A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateraltransfer of iron to the circulation.

McKie AT, Marciani P, Rolfs A, Brennan K, Wehr K, Barrow D, Miret S, Bomford A, Peters TJ, Farzaneh F, Hediger MA, Hentze MW,Simpson RJ.

Source

Department of Molecular Medicine, King's College London, Guy's, King's, St Thomas' School of Medicine, United Kingdom. [email protected]

Abstract

Iron absorption by the duodenal mucosa is initiated by uptake of ferrous Fe(II) iron across the brush border membrane and culminates in transfer of the metal across the basolateral membrane to the portal vein circulation by an unknown mechanism. We describe here the isolation and characterization of a novel cDNA (Ireg1) encoding a duodenal protein that is localized to the basolateral membrane of polarized epithelial cells. Ireg1 mRNA and protein expression are increased under conditions of increased iron absorption, and the 5' UTR of the Ireg1 mRNA contains a functional iron-responsive element (IRE). IREG1stimulates iron efflux following expression in Xenopus oocytes. We conclude that IREG1 represents the long-soughtduodenal iron export protein and is upregulated in the iron overload disease, hereditary hemochromatosis.

http://www.ncbi.nlm.nih.gov/pubmed?term=Mol%20Cell.%202000%20Feb%3B5(2)%3A299-309.%20A%20novel%20duodenal%20iron-regulated%20transporter%2C%20IREG1%2C%20implicated%20in%20the%20basolateraltransfer%20of%20iron%20to%20the%20circulation.%20McKie%20AT%2C%20Marciani%20P%2C%20Rolfs%20A%2C%20Brennan%20K%2C%20Wehr%20K%2C%20Barrow%20D%2C%20Miret%20S%2C%20Bomford%20A%2C%20Peters%20TJ%2C%20Farzaneh%20F%2C%20Hediger%20MA%2C%20Hentze%20MW%2CSimpson%20RJ.%20

BMC Med. 2012 Jan 24;10:8.

Clinical evaluation of iron treatment efficiency among non-anemic but iron-deficient female blood donors: a randomized controlled trial.

Waldvogel S, Pedrazzini B, Vaucher P, Bize R, Cornuz J, Tissot JD, Favrat B.

Source

Blood Transfusion Service of the Swiss Red Cross, Lausanne, Switzerland. [email protected]

Abstract

BACKGROUND:

Iron deficiency without anemia is related to adverse symptoms that can be relieved by supplementation. Since a blood donation can induce such an iron deficiency, we investigated the clinical impact of iron treatment after a blood donation.

METHODS:

One week after donation, we randomly assigned 154 female donors with iron deficiency without anemia, aged below 50 years, to a four-week oral treatment of ferrous sulfate versus a placebo. The main outcome was the change in the level of fatigue before and after the intervention. Aerobic capacity, mood disorder, quality of life, compliance and adverse events were also evaluated. Hemoglobin and ferritin were used as biological markers.

RESULTS:

The effect of the treatment from baseline to four weeks of iron treatment was an increase in hemoglobin and ferritin levels to 5.2 g/L (P < 0.01) and 14.8 ng/mL (P < 0.01), respectively. No significant clinical effect was observed for fatigue (-0.15 points, 95% confidence interval -0.9 points to 0.6 points, P = 0.697) or for other outcomes. Compliance and interruption for side effects was similar in both groups. Additionally, blood donation did not induce overt symptoms of fatigue in spite of the significant biological changes it produces.

CONCLUSIONS:

These data are valuable as they enable us to conclude that donors with iron deficiency without anemia after a blood donation would not clinically benefit from iron supplementation.

http://www.ncbi.nlm.nih.gov/pubmed?term=BMC%20Med.%202012%20Jan%2024%3B10%3A8.%20Clinical%20evaluation%20of%20iron%20treatment%20efficiency%20among%20non-anemic%20but%20iron-deficient%20female%20blood%20donors%3A%20a%20randomized%20controlled%20trial.%20Waldvogel%20S%2C%20Pedrazzini%20B%2C%20Vaucher%20P%2C%20Bize%20R%2C%20Cornuz%20J%2C%20Tissot%20JD%2C%20Favrat%20B.%20

Transplantation. 2012 Apr 27;93(8):822-6.

A randomized controlled trial of intravenous or oral iron for posttransplant anemia in kidney transplantation.

Mudge DW, Tan KS, Miles R, Johnson DW, Badve SV, Campbell SB, Isbel NM, van Eps CL, Hawley CM.

Source

1Department of Nephrology, University of Queensland at Princess Alexandra Hospital, Brisbane, Queensland, Australia. 2Department of Renal Medicine, Logan Hospital, Logan, Queensland, Australia. 3Department of Renal Medicine, Greenslopes Private Hospital, Brisbane, Queensland, Australia.

Abstract

BACKGROUND.: Anemia after kidney transplantation has been associated with poor transplant outcomes. We hypothesized that intravenous (IV) iron may more rapidly correct anemia than oral (PO) iron. METHODS.: One hundred four kidney transplant recipients were prospectively randomized to IV iron polymaltose (500 mg single dose) or PO ferrous sulfate (210 mg elemental iron daily, continuously). The primary outcome was time to resolution of anemia, defined as hemoglobin more than or equal to 11 g/dL. Secondary outcomes included infections, blood transfusions, gastrointestinal side-effects, and acute rejection. RESULTS.: There was no significant difference in the primary outcome comparing IV with PO iron (hazards ratio 1.22; 95% confidence interval 0.82-1.83; P=0.32). The median time to resolution of anemia was 12 days in the IV group versus 21 days in the PO group. There were no differences in infections (20% vs. 24%, P=0.62), acute rejection (8% vs. 6%, P=0.68), blood transfusions (10% vs. 18%, P=0.24), and severe gastrointestinal side-effects (6% vs. 12%, P=0.29) between the IV iron and the PO iron groups. CONCLUSIONS.: We conclude that a single dose of IV iron did not result in more rapid resolution of anemia compared with PO iron. Both IV and PO iron are safe and effective in the management of posttransplant anemia.

http://www.ncbi.nlm.nih.gov/pubmed?term=Transplantation.%202012%20Apr%2027%3B93(8)%3A822-6.%20%20A%20randomized%20controlled%20trial%20of%20intravenous%20or%20oral%20iron%20for%20posttransplant%20anemia%20in%20kidney%20transplantation.%20Mudge%20DW%2C%20Tan%20KS%2C%20Miles%20R%2C%20Johnson%20DW%2C%20Badve%20SV%2C%20Campbell%20SB%2C%20Isbel%20NM%2C%20van%20Eps%20CL%2C%20Hawley%20CM.%20

J Nutr. 2012 Mar;142(3):478-83. Epub 2012 Jan 18

Absorption of iron from ferritin is independent of heme iron and ferrous salts in women and rat intestinal segments.

Theil EC, Chen H, Miranda C, Janser H, Elsenhans B, Núñez MT, Pizarro F, Schümann K.

Source

Children's Hospital Oakland Research Institute, Oakland, CA, USA. [email protected]

Abstract

Ferritin iron from food is readily bioavailable to humans and has the potential for treating iron deficiency. Whether ferritin iron absorption is mechanistically different from iron absorption from small iron complexes/salts remains controversial. Here, we studied iron absorption (RBC (59)Fe) from radiolabeled ferritin iron (0.5 mg) in healthy women with or without non-ferritin iron competitors, ferrous sulfate, or hemoglobin. A 9-fold excess of non-ferritin iron competitor had no significant effect on ferritin iron absorption. Larger amounts of iron (50 mg and a 99-fold excess of either competitor) inhibited iron absorption. To measure transport rates of iron that was absorbed inside ferritin, rat intestinal segments ex vivo were perfused with radiolabeled ferritin and compared to perfusion with ferric nitrilotriacetic (Fe-NTA), a well-studied form of chelated iron. Intestinal transport of iron absorbed inside exogenous ferritin was 14.8% of the rate measured for iron absorbed from chelated iron. In the steady state, endogenous enterocyte ferritin contained >90% of the iron absorbed from Fe-NTA or ferritin. We found that ferritin is a slow release source of iron, readily available to humans or animals, based on RBC iron incorporation. Ferritin iron is absorbed by a different mechanism than iron salts/chelates or heme iron. Recognition of a second, nonheme iron absorption process, ferritin endocytosis, emphasizes the need for more mechanistic studies on ferritin iron absorption and highlights the potential of ferritin present in foods such as legumes to contribute to solutions for global iron deficiency.

http://www.ncbi.nlm.nih.gov/pubmed?term=J%20Nutr.%202012%20Mar%3B142(3)%3A478-83.%20Epub%202012%20Jan%2018%20%20Absorption%20of%20iron%20from%20ferritin%20is%20independent%20of%20heme%20iron%20and%20ferrous%20salts%20in%20women%20and%20rat%20intestinal%20segments.%20Theil%20EC%2C%20Chen%20H%2C%20Miranda%20C%2C%20Janser%20H%2C%20Elsenhans%20B%2C%20N%C3%BA%C3%B1ez%20MT%2C%20Pizarro%20F%2C%20Sch%C3%BCmann%20K.%20%20

J Zhejiang Univ Sci B. 2008 Sep;9(9):707-12.

Availability and toxicity of Fe(II) and Fe(III) in Caco-2 cells.

He WL, Feng Y, Li XL, Wei YY, Yang XE.

Source

Ministry of Education Key Laboratory of Polluted Environmental Remediation and Ecological Health, Zhejiang University, Hangzhou 310029, China.

Abstract

The objective of the present study was to compare the toxicity and availability of Fe(II) and Fe(III) to Caco-2 cells. Cellular damage was studied by measuring cell proliferation and lactate dehydrogenase (LDH) release. The activities of two major antioxidative enzymes [superoxide dismutase (SOD) and glutathione peroxidase (GPx)] and differentiation marker (alkaline phosphatase) were determined after the cells were exposed to different levels of iron salts. The cellular iron concentration was investigated to evaluate iron bioavailability. The results show that iron uptake of the cells treated with Fe(II) is significantly higher than that of the cells treated with Fe(III) (P<0.05). Fe(II) at a concentration >1.5 mmol/L was found to be more effective in reducing cellular viability than Fe(III). LDH release investigation suggests that Fe(II) can reduce stability of the cell membrane. The activities of SOD and GPx of the cells treated with Fe(II) were higher than those of the cells treated withFe(III), although both of them increased with raising iron supply levels. The results indicate that both Fe(II) and Fe(III) could reduce the cellular antioxidase gene expression at high levels.

http://www.ncbi.nlm.nih.gov/pubmed/18763303

Pflugers Arch. 2004 Jul;448(4):431-7. Epub 2004 Apr 28.

Differences in the uptake of iron from Fe(II) ascorbate and Fe(III) citrate by IEC-6 cells and the involvement of ferroportin/IREG-1/MTP-1/SLC40A1.

Thomas C, Oates PS.

Source

Physiology, M311, School of Biomedical and Chemical Sciences, The University of Western Australia, 35 Stirling Highway, WA 6009, Crawley, Australia.

Abstract

Dietary iron is present in the intestine as Fe(II) and Fe(III). Since enterocytes take up Fe(II) by the divalent metal transporter (DMT1), Fe(III) must be reduced. Whether other Fe(III) transport processes are present is unknown. Release of iron from the enterocyte into the plasma involves theiron-regulated transporter-1/metal transporter protein-1 (IREG-1/MTP-1, ferroportin) but ferroportin is also found on the apical membrane. We compared the uptake of iron from Fe(II):ascorbate and Fe(III):citrate using the rat intestinal enterocyte cell line-6 (IEC-6), in the presence of ferrous chelators, a blocking antibody to ferroportin, at different pH and during the over-expression of DMT1. Firstly, surface ferrireduction was absent. Secondly, blocking ferroportin partly and totally reduced Fe(II) and Fe(III) uptake, respectively. Thirdly, optimal Fe(II) uptake occurred at pH 5.5 but Fe(III) uptake was unaffected by pH and, fourthly, over-expression of DMT1 increased uptake of Fe(II) and Fe(III). This indicates that an increased extracellular H+ concentration facilitates DMT1-mediated Fe(II) uptake at the cell membrane. However, since Fe(III) uptakerequired DMT1, but not cell surface ferrireduction, and was independent of variations in extracellular pH, it appears that Fe(III) is internalised before ferrireduction and transport by DMT1. Ferroportin may function as a modulator of DMT1 activity and play a role in Fe(III) uptake, possibly by affecting the number or affinity of citrate binding sites.

http://www.ncbi.nlm.nih.gov/pubmed/15114483