Hepcidin Decreases Iron Transporter Expression in Vivo in Mouse Duodenum and Spleen and in Vitro in THP-1 Macrophages and Intestinal Caco-2 Cells

Chung, Bomee; Chaston, Timothy B.; Marks, Joanne; Srai, Surjit Kaila; Sharp, Paul

doi:10.3945/jn.108.102905

Cited by 67 publications

(57 citation statements)

References 40 publications

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“…At the basolateral membrane, FPN should be carrying its ascribed role of iron export transporter (30), but the presence of FPN in the apical membrane is intriguing. The presence of FPN in apical domains of absorbing enterocytes had been noticed previously (11,44) although no functional role was ascribed to it. The results of this work support a putative role for apical FPN in a retrograde basal-to-apical iron flux in which non-transferrin-bound iron in the blood plasma is transported to the intestinal lumen.…”

Section: Discussionmentioning

confidence: 99%

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

Núñez

Tapia

Rojas³

et al. 2010

American Journal of Physiology-Cell Physiology

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Núñez MT, Tapia V, Rojas A, Aguirre P, Gómez F, Nualart F. Iron supply determines apical/basolateral membrane distribution of intestinal iron transporters DMT1 and ferroportin 1. Am J Physiol Cell Physiol 298: C477-C485, 2010. First published December 9, 2009; doi:10.1152/ajpcell.00168.2009.-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, 55 Fe 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.intestinal iron absorption; divalent metal transporter 1; mucosal block IN THE ABSENCE OF A CONTROLLED excretion mechanism, iron levels in the body are regulated mainly by its passage through the duodenum epithelia. Traditionally, intestinal iron absorption is divided into three sequential steps: the uptake of iron from the intestinal lumen; an intracellular phase, in which iron binds to cytosolic components; and a transfer step, in which iron passes from the cells to the blood plasma. The uptake of iron from the lumen of the intestine is mediated by the Fe 2ϩ -H ϩ cotransporter divalent metal transporter 1 (DMT1) (19).Once inside the enterocyte, iron integrates into a cytosolic pool of weakly bound iron called the labile iron pool (LIP) (16,25). The nature of the LIP-binding counterpart is unknown, but it has been ascribed to diverse low-molecular-weight substances such as phosphate, nucleotides, hydroxyl, amino, and sulfydryl groups (23,36). From the LIP, iron distributes into ferritin and other iron-requiring proteins (15, 24). Iron exit from the enterocyte is mediated by the efflux transporter ferroportin (FPN), the only m...

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Section: Discussionmentioning

confidence: 99%

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

Núñez

Tapia

Rojas³

et al. 2010

American Journal of Physiology-Cell Physiology

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“…The net effect of these differences is the much lower contribution of intestinal iron absorption to the daily iron flux in humans (4%-8% compared with more than 50% in mice). 9 If hepcidin and its analogs exert stronger effects on macrophages than on enterocytes 13 this could further decrease the relative doses of minihepcidins required for a similar hypoferremic effect in humans.…”

Section: Discussionmentioning

confidence: 99%

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

Ramos

Ruchala

Goodnough

et al. 2012

Blood

189

169

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The deficiency of hepcidin, the hormone that controls iron absorption and its tissue distribution, is the cause of iron overload in nearly all forms of hereditary hemochromatosis and in untransfused iron-loading anemias. In a recent study, we reported the development of minihepcidins, small drug-like hepcidin agonists. Here we explore the feasibility of using minihepcidins for the prevention and treatment of iron overload in hepcidindeficient mice. An optimized minihepcidin (PR65) was developed that had superior potency and duration of action compared with natural hepcidin or other minihepcidins, and favorable cost of synthesis. PR65 was administered by subcutaneous injection daily for 2 weeks to iron-depleted or iron-loaded hepcidin knockout mice. PR65 administration to iron-depleted mice prevented liver iron loading, decreased heart iron levels, and caused the expected iron retention in the spleen and duodenum. At high doses, PR65 treatment also caused anemia because of profound iron restriction. PR65 administration to hepcidin knockout mice with pre-existing iron overload had a more moderate effect and caused partial redistribution of iron from the liver to the spleen. Our study demonstrates that minihepcidins could be beneficial in iron overload disorders either used alone for prevention or possibly as adjunctive therapy with phlebotomy or chelation. IntroductionProduced by the liver, hepcidin is a 25 amino acid peptide hormone that circulates in plasma and homeostatically controls body iron balance. 1 Iron levels in turn regulate hepcidin production: in healthy individuals, hepcidin production increases when plasma or tissue iron concentrations rise and decreases after iron depletion. The hormone binds to its receptor ferroportin, the sole exporter of cellular iron into plasma. Ferroportin is prominently expressed in enterocytes, iron-recycling macrophages and hepatocytes. Hepcidin binding initiates the endocytosis and proteolysis of ferroportin and thereby decreases iron flow into plasma. 2 In hereditary hemochromatoses (HH) types I-III, mutations in genes encoding hepcidin regulators, or hepcidin itself lead to diminished production of hepcidin thus decreasing the inhibitory effect of hepcidin on duodenal iron absorption and causing clinical iron overload. 3 Hepcidin deficiency and hyperabsorption of dietary iron are major factors not only in HH but also in iron overload associated with hereditary anemias caused by ineffective erythropoiesis. 4 Hepcidin replacement therapy with pharmacologically optimized agonists would provide a rational treatment for these disorders. In HH or ␤-thalassemia intermedia, early diagnosis may allow preventive treatment with hepcidin agonists to normalize iron regulation, and reduce the potential for iron toxicity and the need for phlebotomy or chelation. Aside from inhibiting dietary iron absorption, hepcidin or hepcidin agonists may also have a protective effect on the liver, heart, and other organs by causing redistribution of iron into macrophages of the liver and spleen...

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“…H ypereosinophilic syndromes (HES) are a group of disorders characterized by persistent and marked hypereosinophilia (>1500 per microliter) not due to an underlying disease known to cause eosinophil expansion (such as an allergic drug reaction or parasitic infection), and which is directly implicated in damage or dysfunction of at least one target organ or tissue. 1,2 Although rare, HES have recently nurtured much interest, as fascinating pathogenic mechanisms have been discovered in patient subgroups, and novel targeted therapeutic approaches have recently been proven efficacious. Efforts are now being directed towards improving diagnostic criteria and classification of disease forms, 2 in order to better reflect these advances, and more importantly to provide physicians with a practical diagnostic approach to patients in whom chronic damage-inducing hypereosinophilia can not be resolved by treating an easily recognized underlying cause.…”

Section: Discussionmentioning

confidence: 99%

“…At the core of this is hepcidin, a small acute phase antimicrobial peptide that now also appears to synchronously orchestrate the response of iron transporter and regulatory genes to ensure proper balance between how much dietary iron is absorbed by the small intestine or released into the circulation by macrophages. 1 Several studies suggest that there are strong genetic components that underlie hepcidin regulation beyond the usual suspects (i.e. infection, inflammation, erythropoiesis, hypoxia and iron), in a manner that could impinge on phenotypic differences in susceptibility to iron-overload or anemia.…”

mentioning

confidence: 99%

Genetic variation in hepcidin expression and its implications for phenotypic differences in iron metabolism

Bayele¹,

Srai²

2009

Haematologica

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Hepcidin Decreases Iron Transporter Expression in Vivo in Mouse Duodenum and Spleen and in Vitro in THP-1 Macrophages and Intestinal Caco-2 Cells

Cited by 67 publications

References 40 publications

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

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

Minihepcidins prevent iron overload in a hepcidin-deficient mouse model of severe hemochromatosis

Genetic variation in hepcidin expression and its implications for phenotypic differences in iron metabolism

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