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Elizabeta Nemeth - One of the best experts on this subject based on the ideXlab platform.
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enteral ferric citrate absorption is dependent on the iron transport protein Ferroportin
Kidney International, 2021Co-Authors: Mark R Hanudel, Victoria Gabayan, Bo Qiao, Brian Czaya, Shirley Wong, Maxime Rappaport, Shweta S Namjoshi, Kristine Chua, Grace Jung, Elizabeta NemethAbstract:Ferric citrate is approved as an iron replacement product in patients with non-dialysis chronic kidney disease and iron deficiency anemia. Ferric citrate-delivered iron is enterally absorbed, but the specific mechanisms involved have not been evaluated, including the possibilities of conventional, transcellular Ferroportin-mediated absorption and/or citrate-mediated paracellular absorption. Here, we first demonstrate the efficacy of ferric citrate in high hepcidin models, including Tmprss6 knockout mice (characterized by iron-refractory iron deficiency anemia) with and without adenine diet-induced chronic kidney disease. Next, to assess whether or not enteral ferric citrate absorption is dependent on Ferroportin, we evaluated the effects of ferric citrate in a tamoxifen-inducible, enterocyte-specific Ferroportin knockout murine model (Villin-Cre-ERT2, Fpnflox/flox). In this model, Ferroportin deletion was efficient, as tamoxifen injection induced a 4000-fold decrease in duodenum Ferroportin mRNA expression, with undetectable Ferroportin protein on Western blot of duodenal enterocytes, resulting in a severe iron deficiency anemia phenotype. In Ferroportin-deficient mice, three weeks of 1% ferric citrate dietary supplementation, a dose that prevented iron deficiency in control mice, did not improve iron status or rescue the iron deficiency anemia phenotype. We repeated the conditional Ferroportin knockout experiment in the setting of uremia, using an adenine nephropathy model, where three weeks of 1% ferric citrate dietary supplementation again failed to improve iron status or rescue the iron deficiency anemia phenotype. Thus, our data suggest that enteral ferric citrate absorption is dependent on conventional enterocyte iron transport by Ferroportin and that, in these models, significant paracellular absorption does not occur.
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Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
'MDPI AG', 2021Co-Authors: Elizabeta Nemeth, Tomas GanzAbstract:Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter Ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through Ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through Ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through Ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to Ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin
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levels of the erythropoietin responsive hormone erythroferrone in mice and humans with chronic kidney disease
Haematologica, 2018Co-Authors: Mark R Hanudel, Victoria Gabayan, Tomas Ganz, Bo Qiao, Maxime Rappaport, Kristine Chua, Grace Jung, Isidro B Salusky, Elizabeta NemethAbstract:Erythroferrone (ERFE) is a hormone produced by human and murine erythroid precursors that acts directly on the liver to decrease hepcidin production.[1][1] Hepcidin regulates circulating iron concentrations by binding to the cellular iron exporter Ferroportin, causing its internalization and
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cellular catabolism of the iron regulatory peptide hormone hepcidin
PLOS ONE, 2013Co-Authors: Gloria C Preza, Tomas Ganz, Rogelio Pinon, Elizabeta NemethAbstract:Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter Ferroportin, induces Ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to Ferroportin. We show that hepcidin is taken up by Ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to Ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both Ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the hormone hepcidin and its receptor Ferroportin are internalized together and trafficked to lysosomes where both are degraded.
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hepcidin induced endocytosis of Ferroportin is dependent on Ferroportin ubiquitination
Cell Metabolism, 2012Co-Authors: Bo Qiao, Tomas Ganz, Priscilla Sugianto, Eileen Fung, Alejandro Delcastillorueda, Mariajosefa Moranjimenez, Elizabeta NemethAbstract:Summary Ferroportin exports iron into plasma from absorptive enterocytes, erythrophagocytosing macrophages, and hepatic stores. The hormone hepcidin controls cellular iron export and plasma iron concentrations by binding to Ferroportin and causing its internalization and degradation. We explored the mechanism of hepcidin-induced endocytosis of Ferroportin, the key molecular event in systemic iron homeostasis. Hepcidin binding caused rapid ubiquitination of Ferroportin in cell lines overexpressing Ferroportin and in murine bone marrow-derived macrophages. No hepcidin-dependent ubiquitination was observed in C326S Ferroportin mutant which does not bind hepcidin. Substitutions of lysines between residues 229 and 269 in the third cytoplasmic loop of Ferroportin prevented hepcidin-dependent ubiquitination and endocytosis of Ferroportin, and promoted cellular iron export even in the presence of hepcidin. The human Ferroportin mutation K240E, previously associated with clinical iron overload, caused hepcidin resistance in vitro by interfering with Ferroportin ubiquitination. Our study demonstrates that ubiquitination is the functionally relevant signal for hepcidin-induced Ferroportin endocytosis.
Tomas Ganz - One of the best experts on this subject based on the ideXlab platform.
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Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis
'MDPI AG', 2021Co-Authors: Elizabeta Nemeth, Tomas GanzAbstract:Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter Ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through Ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through Ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through Ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to Ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin
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erythrocytes and erythroblasts give up iron
Blood, 2018Co-Authors: Tomas GanzAbstract:In this issue of Blood, by comparing wild-type vs erythroid-specific Ferroportin knockout mice, Zhang et al1 have shown that Ferroportin-mediated export of iron from erythroblasts and erythrocytes contributes to the systemic iron economy and prevents hemolysis.
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levels of the erythropoietin responsive hormone erythroferrone in mice and humans with chronic kidney disease
Haematologica, 2018Co-Authors: Mark R Hanudel, Victoria Gabayan, Tomas Ganz, Bo Qiao, Maxime Rappaport, Kristine Chua, Grace Jung, Isidro B Salusky, Elizabeta NemethAbstract:Erythroferrone (ERFE) is a hormone produced by human and murine erythroid precursors that acts directly on the liver to decrease hepcidin production.[1][1] Hepcidin regulates circulating iron concentrations by binding to the cellular iron exporter Ferroportin, causing its internalization and
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systemic iron homeostasis
Physical Review, 2013Co-Authors: Tomas GanzAbstract:The iron hormone hepcidin and its receptor and cellular iron exporter Ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and Ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and Ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation.
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cellular catabolism of the iron regulatory peptide hormone hepcidin
PLOS ONE, 2013Co-Authors: Gloria C Preza, Tomas Ganz, Rogelio Pinon, Elizabeta NemethAbstract:Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter Ferroportin, induces Ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of hepcidin after binding to Ferroportin. We show that hepcidin is taken up by Ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled hepcidin (TR-Hep) was added to Ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both Ferroportin and hepcidin. In addition, using radio-labeled hepcidin and HPLC analysis we show that hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the hormone hepcidin and its receptor Ferroportin are internalized together and trafficked to lysosomes where both are degraded.
Martina U Muckenthaler - One of the best experts on this subject based on the ideXlab platform.
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Modelling Systemic Iron Regulation during Dietary Iron Overload and Acute Inflammation: Role of Hepcidin-Independent Mechanisms
2017Co-Authors: Mihaela Enculescu, Martina U Muckenthaler, Christoph Metzendorf, Richard Sparla, Maximilian Hahnel, Johannes Bode, Stefan LegewieAbstract:Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays Ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to Ferroportin and triggers its degradation. The relative importance of individual Ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/Ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular Ferroportin transcription, and not by hepcidin-dependent Ferroportin protein destabilization. In contrast, Ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional Ferroportin-independent homeostasis mechanisms.
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out of balance systemic iron homeostasis in iron related disorders
Nutrients, 2013Co-Authors: Andrea U Steinbicker, Martina U MuckenthalerAbstract:Iron is an essential element in our daily diet. Most iron is required for the de novo synthesis of red blood cells, where it plays a critical role in oxygen binding to hemoglobin. Thus, iron deficiency causes anemia, a major public health burden worldwide. On the other extreme, iron accumulation in critical organs such as liver, heart, and pancreas causes organ dysfunction due to the generation of oxidative stress. Therefore, systemic iron levels must be tightly balanced. Here we focus on the regulatory role of the hepcidin/Ferroportin circuitry as the major regulator of systemic iron homeostasis. We discuss how regulatory cues (e.g., iron, inflammation, or hypoxia) affect the hepcidin response and how impairment of the hepcidin/Ferroportin regulatory system causes disorders of iron metabolism.
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heme controls Ferroportin1 fpn1 transcription involving bach1 nrf2 and a mare are sequence motif at position 7007 of the fpn1 promoter
Haematologica, 2010Co-Authors: Samuele Marro, Deborah Chiabrando, Erika Messana, Jens Stolte, Emilia Turco, Emanuela Tolosano, Martina U MuckenthalerAbstract:Background Macrophages of the reticuloendothelial system play a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes. Heme oxygenase 1 degrades the heme moiety and releases inorganic iron that is stored in ferritin or exported to the plasma via the iron export protein Ferroportin. In the plasma, iron binds to transferrin and is made available for de novo red cell synthesis. The aim of this study was to gain insight into the regulatory mechanisms that control the transcriptional response of iron export protein Ferroportin to hemoglobin in macrophages. Design and Methods Iron export protein Ferroportin mRNA expression was analyzed in RAW264.7 mouse macrophages in response to hemoglobin, heme, ferric ammonium citrate or protoporphyrin treatment or to siRNA mediated knockdown or overexpression of Btb And Cnc Homology 1 or nuclear accumulation of Nuclear Factor Erythroid 2-like. Iron export protein Ferroportin promoter activity was analyzed using reporter constructs that contain specific truncations of the iron export protein Ferroportin promoter or mutations in a newly identified MARE/ARE element. Results We show that iron export protein Ferroportin is transcriptionally co-regulated with heme oxygenase 1 by heme, a degradation product of hemoglobin. The protoporphyrin ring of heme is sufficient to increase iron export protein Ferroportin transcriptional activity while the iron released from the heme moiety controls iron export protein Ferroportin translation involving the IRE in the 5′untranslated region. Transcription of iron export protein Ferroportin is inhibited by Btb and Cnc Homology 1 and activated by Nuclear Factor Erythroid 2-like involving a MARE/ARE element located at position −7007/−7016 of the iron export protein Ferroportin promoter. Conclusions This finding suggests that heme controls a macrophage iron recycling regulon involving Btb and Cnc Homology 1 and Nuclear Factor Erythroid 2-like to assure the coordinated degradation of heme by heme oxygenase 1, iron storage and detoxification by ferritin, and iron export by iron export protein Ferroportin.
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systemic iron homeostasis and the iron responsive element iron regulatory protein ire irp regulatory network
Annual Review of Nutrition, 2008Co-Authors: Martina U Muckenthaler, Bruno Galy, Matthias W HentzeAbstract:The regulation and maintenance of systemic iron homeostasis is critical to human health. Iron overload and deficiency diseases belong to the most common nutrition-related pathologies across the globe. It is now well appreciated that the hormonal hepcidin/Ferroportin system plays an important regulatory role for systemic iron metabolism. We review recent data that uncover the importance of the cellular iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network in systemic iron homeostasis. We also discuss how the IRE/IRP regulatory system communicates with the hepcidin/Ferroportin system to connect the control networks for systemic and cellular iron balance.
Jerry Kaplan - One of the best experts on this subject based on the ideXlab platform.
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Ferroportin mediated iron transport expression and regulation
Biochimica et Biophysica Acta, 2012Co-Authors: Diane M. Ward, Jerry KaplanAbstract:The distinguishing feature between iron homeostasis in single versus multicellular organisms is the need for multicellular organisms to transfer iron from sites of absorption to sites of utilization and storage. Ferroportin is the only known iron exporter and Ferroportin plays an essential role in the export of iron from cells to blood. Ferroportin can be regulated at many different levels including transcriptionally, post-transcriptionally, through mRNA stability and post-translationally, through protein turnover. Additionally, Ferroportin may be regulated in both cell-dependent and cell-autonomous fashions. Regulation of Ferroportin is critical for iron homeostasis as alterations in Ferroportin may result in either iron deficiency or iron overload. This article is part of a Special Issue entitled: Cell Biology of Metals.
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The molecular basis of iron overload disorders and iron-linked anemias
International Journal of Hematology, 2011Co-Authors: Jerry Kaplan, Diane M. Ward, Ivana De DomenicoAbstract:Iron homeostasis in vertebrates requires coordination between cells that export iron into plasma and those that utilize or store plasma iron. The coordination of iron acquisition and utilization is mediated by the interaction of the peptide hormone hepcidin and the iron exporter Ferroportin. Hepcidin levels are increased during iron sufficiency and inflammation and are decreased in hypoxia or erythropoiesis. Hepcidin is a negative regulator of iron export. Hepcidin binds to cell surface Ferroportin inducing Ferroportin degradation and decreasing cellular iron export. Genetic disorders of iron overload of iron-linked anemia can be explained by changes in the level of hepcidin or Ferroportin and of the ability of Ferroportin to be internalized by hepcidin.
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hepcidin mediates transcriptional changes that modulate acute cytokine induced inflammatory responses in mice
Journal of Clinical Investigation, 2010Co-Authors: Ivana De Domenico, Diane M. Ward, Tian Y Zhang, Curry L Koening, Ryan W Branch, Nyall London, Raymond A Daynes, James P Kushner, Jerry KaplanAbstract:Hepcidin is a peptide hormone that regulates iron homeostasis and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter Ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of Ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of Ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-α transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses.
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the Ferroportin metal efflux proteins function in iron and cobalt homeostasis in arabidopsis
The Plant Cell, 2009Co-Authors: Joe Morrissey, Jerry Kaplan, Ivan Baxter, Joohyun Lee, Brett Lahner, Natasha Grotz, David E Salt, Mary Lou GuerinotAbstract:Relatively little is known about how metals such as iron are effluxed from cells, a necessary step for transport from the root to the shoot. Ferroportin (FPN) is the sole iron efflux transporter identified to date in animals, and there are two closely related orthologs in Arabidopsis thaliana, IRON REGULATED1 (IREG1/FPN1) and IREG2/FPN2. FPN1 localizes to the plasma membrane and is expressed in the stele, suggesting a role in vascular loading; FPN2 localizes to the vacuole and is expressed in the two outermost layers of the root in response to iron deficiency, suggesting a role in buffering metal influx. Consistent with these roles, fpn2 has a diminished iron deficiency response, whereas fpn1 fpn2 has an elevated iron deficiency response. Ferroportins also play a role in cobalt homeostasis; a survey of Arabidopsis accessions for ionomic phenotypes showed that truncation of FPN2 results in elevated shoot cobalt levels and leads to increased sensitivity to the metal. Conversely, loss of FPN1 abolishes shoot cobalt accumulation, even in the cobalt accumulating mutant frd3. Consequently, in the fpn1 fpn2 double mutant, cobalt cannot move to the shoot via FPN1 and is not sequestered in the root vacuoles via FPN2; instead, cobalt likely accumulates in the root cytoplasm causing fpn1 fpn2 to be even more sensitive to cobalt than fpn2 mutants.
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Iron-depletion limits intracellular bacterial growth in macrophages
Blood, 2008Co-Authors: P Paradkar, I Zohn, Ivana De Domenico, Jerry Kaplan, Nina Durchfort, Diane M. WardAbstract:Many intracellular pathogens infect macrophages and these pathogens require iron for growth. Here we demonstrate in vitro that the intracellular growth of Chlamydia psittaci, Chlamydia trachomatis and Legionella pneumophila is regulated by the levels of intracellular iron. Macrophages that express cell surface Ferroportin, the only known cellular iron exporter, limit the intracellular growth of these bacteria. Hepcidin is an anti-microbial peptide secreted by the liver in response to inflammation. Hepcidin binds to Ferroportin mediating its internalization and degradation. Addition of hepcidin to infected macrophages enhanced the intracellular growth of these pathogens. Macrophages from flatiron mice, a strain heterozygous for a loss-of-function Ferroportin mutation, showed enhanced intracellular bacterial growth independent of the presence of exogenous hepcidin. Macrophages, from wild type or flatiron mice, incubated with the oral iron chelators deferriprone or desferasirox showed reduced intracellular bacterial growth suggesting that these chelators might be therapeutic in chronic intracellular bacterial infections.
Adriana Donovan - One of the best experts on this subject based on the ideXlab platform.
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the iron exporter Ferroportin slc40a1 is essential for iron homeostasis
Cell Metabolism, 2005Co-Authors: Jack L Pinkus, Geraldine S Pinkus, Adriana Donovan, Christine A Lima, Leonard I Zon, Sylvie RobineAbstract:Ferroportin (SLC40A1) is an iron transporter postulated to play roles in intestinal iron absorption and cellular iron release. Hepcidin, a regulatory peptide, binds to Ferroportin and causes it to be internalized and degraded. If Ferroportin is the major cellular iron exporter, ineffective hepcidin function could explain manifestations of human hemochromatosis disorders. To investigate this, we inactivated the murine Ferroportin (Fpn) gene globally and selectively. Embryonic lethality of Fpn(null/null) animals indicated that Ferroportin is essential early in development. Rescue of embryonic lethality through selective inactivation of Ferroportin in the embryo proper suggested that Ferroportin has an important function in the extraembryonic visceral endoderm. Ferroportin-deficient animals accumulated iron in enterocytes, macrophages, and hepatocytes, consistent with a key role for Ferroportin in those cell types. Intestine-specific inactivation of Ferroportin confirmed that it is critical for intestinal iron absorption. These observations define the major sites of Ferroportin activity and give insight into hemochromatosis.
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hepcidin regulates cellular iron efflux by binding to Ferroportin and inducing its internalization
Science, 2004Co-Authors: Elizabeta Nemeth, Diane M. Ward, Tomas Ganz, Adriana Donovan, Marie S Tuttle, Julie Powelson, Michael B Vaughn, Jerry KaplanAbstract:Hepcidin is a peptide hormone secreted by the liver in response to iron loading and inflammation. Decreased hepcidin leads to tissue iron overload, whereas hepcidin overproduction leads to hypoferremia and the anemia of inflammation. Ferroportin is an iron exporter present on the surface of absorptive enterocytes, macrophages, hepatocytes, and placental cells. Here we report that hepcidin bound to Ferroportin in tissue culture cells. After binding, Ferroportin was internalized and degraded, leading to decreased export of cellular iron. The posttranslational regulation of Ferroportin by hepcidin may thus complete a homeostatic loop: Iron regulates the secretion of hepcidin, which in turn controls the concentration of Ferroportin on the cell surface.
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autosomal dominant hemochrom atosis is associated with a mutation in the Ferroportin slc11a3 gene
Journal of Clinical Investigation, 2001Co-Authors: Giuliana Montosi, Nancy C Andrews, Adriana Donovan, A Totaro, Cinzia Garuti, Elisa Pignatti, Stefano Cassanelli, Cameron C Trenor, Paolo Gasparini, Antonello PietrangeloAbstract:Hemochromatosis is a progressive iron overload disorder that is prevalent among individuals of European descent. It is usually inherited in an autosomal-recessive pattern and associated with missense mutations in HFE, an atypical major histocompatibility class I gene. Recently, we described a large family with autosomal-dominant hemochromatosis not linked to HFE and distinguished by early iron accumulation in reticuloendothelial cells. Through analysis of a large pedigree, we have determined that this disease maps to 2q32. The gene encoding Ferroportin (SLC11A3), a transmembrane iron export protein, lies within a candidate interval defined by highly significant lod scores. We show that the iron-loading phenotype in autosomal-dominant hemochromatosis is associated with a nonconservative missense mutation in the Ferroportin gene. This missense mutation, converting alanine to aspartic acid at residue 77 (A77D), was not seen in samples from 100 unaffected control individuals. We propose that partial loss of Ferroportin function leads to an imbalance in iron distribution and a consequent increase in tissue iron accumulation.
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positional cloning of zebrafish Ferroportin1 identifies a conserved vertebrate iron exporter
Nature, 2000Co-Authors: Adriana Donovan, Alison Brownlie, Yi Zhou, Jennifer L Shepard, Stephen J Pratt, John Moynihan, Barry H Paw, Anna Drejer, Bruce A BarutAbstract:Defects in iron absorption and utilization lead to iron deficiency and overload disorders. Adult mammals absorb iron through the duodenum, whereas embryos obtain iron through placental transport. Iron uptake from the intestinal lumen through the apical surface of polarized duodenal enterocytes is mediated by the divalent metal transporter, DMT1 (refs 1,2,3). A second transporter has been postulated to export iron across the basolateral surface to the circulation. Here we have used positional cloning to identify the gene responsible for the hypochromic anaemia of the zebrafish mutant weissherbst. The gene, Ferroportin1, encodes a multiple-transmembrane domain protein, expressed in the yolk sac, that is a candidate for the elusive iron exporter. Zebrafish Ferroportin1 is required for the transport of iron from maternally derived yolk stores to the circulation and functions as an iron exporter when expressed in Xenopus oocytes. Human Ferroportin1 is found at the basal surface of placental syncytiotrophoblasts, suggesting that it also transports iron from mother to embryo. Mammalian Ferroportin1 is expressed at the basolateral surface of duodenal enterocytes and could export cellular iron into the circulation. We propose that Ferroportin1 function may be perturbed in mammalian disorders of iron deficiency or overload.