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Tortosa, Valentina, Maria Carmela Bonaccorsi di Patti, Giovanni Musci, and Fabio Polticelli. "The human iron exporter ferroportin. Insight into the transport mechanism by molecular modeling." Bio-Algorithms and Med-Systems 12, no. 1 (January 1, 2016): 1–7. http://dx.doi.org/10.1515/bams-2015-0034.
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AbstractFerroportin, a membrane protein belonging to the major facilitator superfamily of transporters, is the only vertebrate iron exporter known so far. Several ferroportin mutations lead to the so-called ferroportin disease or type 4 hemochromatosis, characterized by two distinct iron accumulation phenotypes depending on whether the mutation affects the activity of the protein or its degradation pathway. Through extensive molecular modeling analyses using the structure of all known major facilitator superfamily members as templates, multiple structural models of ferroportin in the three mechanistically relevant conformations (inward open, occluded, and outward open) have been obtained. The best models, selected on the ground of experimental data available on wild-type and mutant ferroportion, provide for the first time a prediction at the atomic level of the dynamics of the transporter. Based on these results, a possible mechanism for iron export is proposed.
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Chlosta, Sabine, Douglas S. Fishman, Lynne Harrington, Erin E. Johnson, Mitchell D. Knutson, Marianne Wessling-Resnick, and Bobby J. Cherayil. "The Iron Efflux Protein Ferroportin Regulates the Intracellular Growth of Salmonella enterica." Infection and Immunity 74, no. 5 (May 2006): 3065–67. http://dx.doi.org/10.1128/iai.74.5.3065-3067.2006.
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ABSTRACT We investigated the influence of the macrophage iron exporter ferroportin and its ligand hepcidin on intracellular Salmonella growth. Elevated ferroportin expression inhibited bacterial multiplication; hepcidin-induced ferroportin down-regulation enhanced it. Expression analysis of iron-responsive Salmonella genes indicated ferroportin-mediated iron deprivation. These results demonstrate a role for ferroportin in antimicrobial resistance.
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Ammosova, Tatiana, Andrey Ivanov, and Sergei A. Nekhai. "Ferroportin Q248H Mutation Prevents Its Ubiquitination." Blood 122, no. 21 (November 15, 2013): 2196. http://dx.doi.org/10.1182/blood.v122.21.2196.2196.
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Abstract Background Ferroportin Q248H mutation is prevalent in African populations and leads to increased serum ferritin. Our recent study shows that ferroportin Q248H protein is resistant to physiologic hepcidin concentrations1. Also sickle cell disease patients with ferroportin Q248H heterozygote had lower serum ferritin concentration suggesting that the enhanced iron release by macrophages. Ferroportin glutamine 248 is located within the intracellular loop (residues 228-307), which is likely to be located in the cytoplasm. Recently ferroportin internalization was shown to be driven by ubiquitination of lysines lying within residues 229-269 including K229, K240, and K2472. The proximity of the K240 and especially to K247 to the Q248 residue suggests that a positively charged histidine in position 248 might change the overall negative charge of the 240eeetelkqlnlhk253sequence toward a more positive charge, which might affect ubiquitination and subsequent degradation of ferroportin. Here we analyzed and compared ubiquitination of WT and Q248H mutant ferroportin. Results WT ferroportin and Q248H mutant were expressed as EGFP-fusions in 293T cells and also combined with the expression of ubiquitin. Ferroportin was immunoprecipitated with anti-EGFP antibodies and analyzed by high resolution mass spectrometry using LTQ-Orbitrap. Phosphorylation and ubiquitination was determined using Proteome Discover and quantified using SIEVE 2.1 software. Conclusions WT ferroportin but not the Q248H mutant ferroportin was found to be ubquitinated on lysines 247 and 253 and also phosphorylated on Thr 144. Also WT ferroportin was found to associate with ubiquitine-conjugating enzyme E2 and ubiquitine protein ligase NEDD4. Thus hepcidin resistance of ferroportin Q248H could be due to its inability to undergo ubiquitination. Acknowledgments This project was supported by NIH Research Grants 8G12MD007597 and P30HL107253. References 1. Nekhai S, Xu M, Foster A, et al. Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin. Haematologica. 2013;98(3):455-463. 2. Qiao B, Sugianto P, Fung E, et al. Hepcidin-induced endocytosis of ferroportin is dependent on ferroportin ubiquitination. Cell Metab. 2012;15(6):918-924. Disclosures: No relevant conflicts of interest to declare.
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Nekhai, Sergei, Namita Kumari, Min Xu, Altreisha Foster, Sharmin Diaz, and Victor R. Gordeuk. "Ferroportin Q248H Mutation Protects From HIV-1 Infection in Vitro." Blood 120, no. 21 (November 16, 2012): 993. http://dx.doi.org/10.1182/blood.v120.21.993.993.
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Abstract Abstract 993 Ferroportin is the only iron exporter expressed in mammalian cells, and hepcidin produced by the liver binds to ferroportin leading to its internalization and degradation by lysosomes. We recently reported that expression of ferroportin in 293T cells transfected with HIV-1 LTR-LacZ and Tat expression vector led to decreased HIV transcription, possibly by reducing availability of intracellular iron, and that exposure to hepcidin restored HIV transcription1. The Q248H mutation in ferroportin has an allele frequency of 2.2–13.4% in African populations and is associated with a mild tendency to increased serum ferritin in the general population. The ferroportin Q248H mutation was reported to associate with lower hepcidin levels in HIV-1 infected Rwandese women2. We also recently showed that ferroportin Q248H mutant has reduced sensitivity to physiologic hepcidin concentrations. We expressed WT and Q248H mutant ferroportin in 293T cells that express very low levels of endogenous ferroportin. We also expressed ferroportin C326Y, a mutant that is not sensitive to hepcidin. We analyzed the effect of ferroportin Q248H on cellular Intracellular ferritin levels which reflect the amount of iron stored within the cells. 293T cells were transfected with ferroportin expressing vectors, incubated with ferric ammonium citrate as a source of iron, pretreated with cycloheximide to stop de-novo protein synthesis and then treated with 30 nM hepcidin. Ferritin levels increased significantly in the cells expressing WT ferroportin and treated with hepcidin (Fig.1A). In contrast, ferritin levels remained the same in untreated and hepcidin treated cells expressing ferroportin Q248H or C326Y (Fig.1A). This observation suggests continuing iron export by ferroportin Q248H with low dose hepcidin. HIV-1 transcription can be induced in 293T cells by co-expression of HIV-1 LTR reporter construct and HIV-1 Tat expression vector (Fig.1B, lane 2). HIV-1 Tat binds to TAR RNA located in the beginning of HIV-1 transcript and facilitates a recruitment of a host cell transcription elongation factor, CDK9/cyclin T1, inducing efficient elongation of HIV-1 transcription. Expression of ferroportin WT, Q248H or C326Y mutant inhibited Tat –induced HIV-1 transcription in comparison to non-relevant control (Fig.1B, lanes 3, 4, 6 and 8). Treatment with physiological hepcidin concentrations reversed the inhibition of Tat-induced HIV-1 transcription by WT but not the Q248H or C326Y mutant ferroportin (Fig.1B, lanes 5, 7 and 9). In this experiment, we utilized c-myc tagged ferroportin expression vectors as in our previous study1. We also obtained very similar results with EGFP-fused ferroportin expression, which also allowed an easier detection of reduction in ferroportin expression in the presence of hepcidin. Finally, we also isolated monocytes from two subjects, one with heterozygote and one with homozygote ferroportin Q248H. Monocytes were infected ex-vivo with pseudotyped HIV-1 virus expressing luciferase. HIV-1 replication was reduced in primary monocytes with heterozygote and homozygote ferroportin Q248H as compared to a control. Ferroportin glutamine 248 is located within the intracellular loop (residues 228–307), in close proximity to lysine residues 229–269 which ubiquitination promotes ferroportin internalization3. Future studies should address the details of ubiquitination of human ferroportin Q248H compared to WT ferroportin. An added protection value could be observed lower hepcidin expression levels in HIV-1 infected individuals with the ferroportin Q248H2. Further studies are needed to uncover a mechanism of this reduced hepcidin expression. Further molecular analysis is needed to understand the mechanism of ferroportin Q248H internalization. Taken together, our study shows that the ferroportin Q248H that has a reduced sensitivity to hepcidin may offer an additional protection from HIV-1. Acknowledgments. This work was supported NIH Research Grants SC1GM082325, R25 HL003679, 2G12RR003048, 8G12MD007597, K25GM097501 and 1P30HL107253. Disclosures: No relevant conflicts of interest to declare.
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Delaby, Constance, Nathalie Pilard, Ana Sofia Gonçalves, Carole Beaumont, and François Canonne-Hergaux. "Presence of the iron exporter ferroportin at the plasma membrane of macrophages is enhanced by iron loading and down-regulated by hepcidin." Blood 106, no. 12 (December 1, 2005): 3979–84. http://dx.doi.org/10.1182/blood-2005-06-2398.
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Ferroportin, the only mammalian iron exporter identified to date, is highly expressed in duodenal enterocytes and in macrophages. Several lines of evidence indicate that in enterocytes the iron export mediated by ferroportin occurs and is regulated at the basolateral cell surface, where the transporter is strongly expressed. By contrast, in macrophages, ferroportin has been shown in intracellular vesicles. We used a high-affinity antibody to specify the localization of endogenous ferroportin expressed in primary culture of bone marrow–derived macrophages, in both basal and induced conditions. Our observations indicate that ferroportin is expressed in vesicular compartments that can reach the plasma membrane of macrophages. Of importance, when ferroportin expression was up-regulated through iron treatment or erythrophagocytosis, ferroportin expression was strongly enhanced at the plasma membrane of macrophages. Moreover, hepcidin dramatically reduced macrophage ferroportin protein levels. At the subcellular level, hepcidin was shown to induce rapid internalization and degradation of the macrophage iron exporter. These data are consistent with a direct iron export by ferroportin through the plasma membrane of macrophages and strongly support an efficient posttranscriptional down-regulation of ferroportin by hepcidin in these cells.
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Li, Shuang, Yihu Yang, and Weikai Li. "Human ferroportin mediates proton-coupled active transport of iron." Blood Advances 4, no. 19 (October 2, 2020): 4758–68. http://dx.doi.org/10.1182/bloodadvances.2020001864.
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Abstract As the sole iron exporter in humans, ferroportin controls systemic iron homeostasis through exporting iron into the blood plasma. The molecular mechanism of how ferroportin exports iron under various physiological settings remains unclear. Here we found that purified ferroportin incorporated into liposomes preferentially transports Fe2+ and exhibits lower affinities of transporting other divalent metal ions. The iron transport by ferroportin is facilitated by downhill proton gradients at the same direction. Human ferroportin is also capable of transporting protons, and this activity is tightly coupled to the iron transport. Remarkably, ferroportin can conduct active transport uphill against the iron gradient, with favorable charge potential providing the driving force. Targeted mutagenesis suggests that the iron translocation site is located at the pore region of human ferroportin. Together, our studies enhance the mechanistic understanding by which human ferroportin transports iron and suggest that a combination of electrochemical gradients regulates iron export.
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Wallace, Daniel F., Jonathan M. Harris, and V. Nathan Subramaniam. "Functional analysis and theoretical modeling of ferroportin reveals clustering of mutations according to phenotype." American Journal of Physiology-Cell Physiology 298, no. 1 (January 2010): C75—C84. http://dx.doi.org/10.1152/ajpcell.00621.2008.
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Ferroportin disease is a heterogeneous iron release disorder resulting from mutations in the ferroportin gene. Ferroportin protein is a multitransmembrane domain iron transporter, responsible for iron export from cells, which, in turn, is regulated by the peptide hormone hepcidin. Mutations in the ferroportin gene may affect either regulation of the protein's transporter function or the ability of hepcidin to regulate iron efflux. We have used a combination of functional analysis of epitope-tagged ferroportin variants coupled with theoretical modeling to dissect the relationship between ferroportin mutations and their cognate phenotypes. Myc epitope-tagged human ferroportin expression constructs were transfected into Caco-2 intestinal cells and protein localization analyzed by immunofluorescence microscopy and colocalization with organelle markers. The effect of mutations on iron efflux was assessed by costaining with anti-ferritin antibodies and immunoblotting to quantitate cellular expression of ferritin and transferrin receptor 1. Wild-type ferroportin localized mainly to the cell surface and intracellular structures. All ferroportin disease-causing mutations studied had no effect on localization at the cell surface. N144H, N144T, and S338R mutant ferroportin retained the ability to transport iron. In contrast, A77D, V162Δ, and L170F mutants were iron transport defective. Surface staining experiments showed that both ends of the protein were located inside the cell. These data were used as the basis for theoretical modeling of the ferroportin molecule. The model predicted phenotypic clustering of mutations with gain-of-function variants associated with a hypothetical channel through the axis of ferroportin. Conversely, loss-of-function variants were located at the membrane/cytoplasm interface.
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Berezovsky, Betty, Jana Frýdlová, Iuliia Gurieva, Daniel W. Rogalsky, Martin Vokurka, and Jan Krijt. "Heart Ferroportin Protein Content Is Regulated by Heart Iron Concentration and Systemic Hepcidin Expression." International Journal of Molecular Sciences 23, no. 11 (May 24, 2022): 5899. http://dx.doi.org/10.3390/ijms23115899.
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The purpose of the study was to investigate the expression of ferroportin protein following treatments that affect systemic hepcidin. Administration of erythropoietin to C57BL/6J mice decreased systemic hepcidin expression; it also increased heart ferroportin protein content, determined by immunoblot in the membrane fraction, to approximately 200% of control values. This increase in heart ferroportin protein is very probably caused by a decrease in systemic hepcidin expression, in accordance with the classical regulation of ferroportin by hepcidin. However, the control of heart ferroportin protein by systemic hepcidin could apparently be overridden by changes in heart non-heme iron content since injection of ferric carboxymaltose to mice at 300 mg Fe/kg resulted in an increase in liver hepcidin expression, heart non-heme iron content, and also a threefold increase in heart ferroportin protein content. In a separate experiment, feeding an iron-deficient diet to young Wistar rats dramatically decreased liver hepcidin expression, while heart non-heme iron content and heart ferroportin protein content decreased to 50% of controls. It is, therefore, suggested that heart ferroportin protein is regulated primarily by the iron regulatory protein/iron-responsive element system and that the regulation of heart ferroportin by the hepcidin-ferroportin axis plays a secondary role.
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De Domenico, Ivana, Michael B. Vaughn, Donghoon Yoon, James P. Kushner, Diane M. Ward, and Jerry Kaplan. "Zebrafish as a model for defining the functional impact of mammalian ferroportin mutations." Blood 110, no. 10 (November 15, 2007): 3780–83. http://dx.doi.org/10.1182/blood-2007-07-100248.
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Abstract The term hemochromatosis represents a group of inherited disorders leading to iron overload. Mutations in HFE, HJV, and TfR2 cause autosomal-recessive forms of hemochromatosis. Mutations in ferroportin, however, result in dominantly inherited iron overload. Some mutations (H32R and N174I) in ferroportin lead to macrophage iron loading, while others (NI44H) lead to hepatocyte iron loading. Expression of H32R or N174I ferroportin cDNA in zebrafish leads to severe iron-limited erythropoiesis. Expression of wild-type ferroportin or hepcidin-resistant ferroportin (N144H) does not affect erythropoiesis. Zebrafish provides a facile way of identifying which ferroportin mutants may lead to macrophage iron loading.
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Galicia-Poblet, Gonzalo, Ester Cid-París, Nerea López-Andrés, Alba Losada-Pajares, Juan-Carlos Jurado-López, María-Isabel Moreno-Carralero, and María-Josefa Morán-Jiménez. "Pediatric Ferroportin Disease." Journal of Pediatric Gastroenterology and Nutrition 63, no. 6 (December 2016): e205-e207. http://dx.doi.org/10.1097/mpg.0000000000000648.
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Pietrangelo, A. "The ferroportin disease." Blood Cells, Molecules, and Diseases 32, no. 1 (February 2004): 131–38. http://dx.doi.org/10.1016/j.bcmd.2003.08.003.
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Drakesmith, Hal, Elizabeta Nemeth, and Tomas Ganz. "Ironing out Ferroportin." Cell Metabolism 22, no. 5 (November 2015): 777–87. http://dx.doi.org/10.1016/j.cmet.2015.09.006.
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Pietrangelo, Antonello. "The ferroportin disease." Clinical Liver Disease 3, no. 5 (May 2014): 98–100. http://dx.doi.org/10.1002/cld.340.
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Qiao, Bo, Priscilla Sugianto, Eileen Fung, Alejandro del-Castillo-Rueda, Maria-Josefa Moran-Jimenez, Tomas Ganz, and Elizabeta Nemeth. "Hepcidin-Induced Endocytosis of Ferroportin Is Dependent on Ferroportin Ubiquitination." Cell Metabolism 15, no. 6 (June 2012): 918–24. http://dx.doi.org/10.1016/j.cmet.2012.03.018.
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Mitchell, Colin J., Ali Shawki, Tomas Ganz, Elizabeta Nemeth, and Bryan Mackenzie. "Functional properties of human ferroportin, a cellular iron exporter reactive also with cobalt and zinc." American Journal of Physiology-Cell Physiology 306, no. 5 (March 1, 2014): C450—C459. http://dx.doi.org/10.1152/ajpcell.00348.2013.
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Iron homeostasis is achieved by regulating the intestinal absorption of the metal and its recycling by macrophages. Iron export from enterocytes or macrophages to blood plasma is thought to be mediated by ferroportin under the control of hepcidin. Although ferroportin was identified over a decade ago, little is understood about how it works. We expressed in Xenopus oocytes a human ferroportin-enhanced green fluorescent protein fusion protein and observed using confocal microscopy its exclusive plasma-membrane localization. As a first step in its characterization, we established an assay to detect functional expression of ferroportin by microinjecting oocytes with 55Fe and measuring efflux. Ferroportin expression increased the first-order rate constants describing 55Fe efflux up to 300-fold over control. Ferroportin-mediated 55Fe efflux was saturable, temperature-dependent (activation energy, Ea ≈ 17 kcal/mol), maximal at extracellular pH ≈ 7.5, and inactivated at extracellular pH < 6.0. We estimated that ferroportin reacts with iron at its intracellular aspect with apparent affinity constant < 10−7 M. Ferroportin expression also stimulated efflux of 65Zn and 57Co but not of 64Cu, 109Cd, or 54Mn. Hepcidin treatment of oocytes inhibited efflux of 55Fe, 65Zn, and 57Co. Whereas hepcidin administration in mice resulted in a marked hypoferremia within 4 h, we observed no effect on serum zinc levels in those same animals. We conclude that ferroportin is an iron-preferring cellular metal-efflux transporter with a narrow substrate profile that includes cobalt and zinc. Whereas hepcidin strongly regulated serum iron levels in the mouse, we found no evidence that ferroportin plays an important role in zinc homeostasis.
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Lakhal-Littleton, Samira. "Ferroportin Mediated Control of Iron Metabolism and Disease." Blood 128, no. 22 (December 2, 2016): SCI—21—SCI—21. http://dx.doi.org/10.1182/blood.v128.22.sci-21.sci-21.
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Abstract Ferroportin, the only known mammalian iron export protein, releases iron from the duodenum, reticuloendothelial system and liver, the sites of iron absorption, recycling and storage respectively. By downregulating ferroportin, the liver-derived hormone hepcidin controls systemic iron availability in response to erythroid demand and inflammation. This ferroportin/hepcidin axis has long been recognized as essential for systemic iron homeostasis. However, both ferroportin and hepcidin are found in tissues not recognized for their role in systemic iron control, such as the heart, the kidney, the brain and the placenta. Co-existence within the same tissue suggests a possible function for hepcidin and ferroportin in local iron homeostasis. However, this hypothesis has not been formally explored. Using mouse models with cardiac-specific manipulation of hepcidin and ferroportin, we have uncovered a role for the cardiac hepcidin/ferroportin axis in cell-autonomous iron homeostasis within cardiomyocytes. Disruption of this cardiac pathway leads to fatal cardiac dysfunction, even against a background of normal systemic iron homeostasis. One the one hand, loss of cardiac ferroportin causes by fatal cardiac iron overload that is preventable by dietary iron restriction 1. On the other hand, loss of cardiac hepcidin or of cardiac hepcidin responsiveness causes fatal cardiomyocyte iron deficiency that is preventable by intravenous iron administration. Comparative study of cardiac iron homeostasis and function in cardiac versus systemic models of ferroportin/hepcidin disruption provides insight into the interplay between systemic and cellular iron homeostasis. A role for the hepcidin/ferroportin axis in cell-autonomous iron control, demonstrated here in the context of the heart, has not previously been described in any other tissue. A pertinent question is whether our findings in the heart extend to other tissues that express both hepcidin and ferroportin, such as the kidney, brain and placenta. Disturbances in iron homeostasis are of clinical importance in cardiovascular disease, renal failure, neurodegeneration and developmental defects. Our findings have two clinically relevant implications: a) that disruption of the local hepcidin/ferroportin axis may in itself have a disease-modifying effect, and b) that therapeutic strategies developed to target the systemic hepcidin/ferroportin axis may have off-target effects relating to local iron control within some tissues. Reference 1.Lakhal-Littleton S, Wolna M, Carr C, et al. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. PNAS. 2015; 10;112(10):3164-3169. Disclosures No relevant conflicts of interest to declare.
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Kumari, Namita, Seyed Mehdi Nouraie, Hatajai Lassiter, Asrar Ahmad, Kathryn Anastos, Jason Lazar, Seble Kassaye, et al. "Control of HIV-1 Infection By Ferroportin Q248H Mutation." Blood 134, Supplement_1 (November 13, 2019): 953. http://dx.doi.org/10.1182/blood-2019-128685.
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BACKGROUND: We recently showed that patients with Sickle Cell Disease (SCD), a hereditary hemolytic disorder, have low incidence of HIV-1 infection [1] and reduced ex vivo HIV-1 infection [2]. PBMC from SCD patients exhibited increased expression of iron export protein, ferroportin and reduced cellular iron levels leading to CDK2 inhibition, reduced SAMHD1 phosphorylation and increased expression of IkBα. Ferroportin expression is regulated by liver-produced hepcidin that facilitates ferroportin internalization and degradation. Ferroportin Q248H mutation has an allele frequency of 2.2-13.4% in African populations. We previously reported reduced sensitivity of ferroportin Q248H mutant to physiologic hepcidin concentrations in patients with sickle cell disease [3]. OBJECTIVES: To analyze the effect of ferroportin Q248H mutation on HIV-1 infection in vitro and in disease progression among a cohort of HIV-1 infected African-American women. METHODS: HEK293 cells were used to express ferroportin Q248H mutant and test cellular ferritin and intracellular labile iron using calcein-AM. Confocal microscopy was used to visualize ferroportin expression. HIV-1 transcription was measured in 293T cells transfected with HIV-1 LTR-Luciferase vector and Tat expressing vector. Ex vivo infection was analyzed in monocyte-derived macrophages infected with VSVg-pseudotyped HIV-1 virus. Ferroportin Q248H mutation was genotyped using Thermo Fisher probe (C_25753769_10) and genotyping services at University of Utah. RESULTS: We observed reduced intracellular iron in ferroportin Q248H expressing cells compared to WT ferroportin even when the cells were treated with hepcidin. In the absence of hepcidin, both WT ferroportin and Q248H ferroportin efficiently inhibited HIV-1 transcription and replication. Hepcidin induced HIV-1 transcription and replication in the cells with WT ferroportin but not Q248H mutant ferroportin. HIV-1 replication was reduced in primary macrophages obtained from patients with ferroportin Q248H mutation. To test whether expression of ferroportin Q248H offered protection from HIV-1 infection, we analyzed a cohort of HIV-1 infected women (WIHS). We genotyped 970 African-American subjects of whom 628 were HIV-1 infected and 342 were non-infected. The prevalence of Q248H hetero or homozygote mutations was 7.0% in non-infected and 11.8% among HIV-1 infected individuals (Odds Ratio=1.77, p=0.02). Analysis of HIV viral load showed significant lower viral load in the subjects with ferroportin Q248H mutation compared to WT. CONCLUSIONS: Our findings point to the contribution of iron metabolism in HIV-1 restriction and the potential role of the ferroportin Q248H mutation in the regulation of HIV-1 infection in vivo. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, 5G12MD007597 and P30AI087714). We thank Women's Interagency HIV-1 study (WIHS) for sharing DNA samples and providing access to the clinical data. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. REFERENCES: Nouraie M, Nekhai S, Gordeuk VR. Sickle cell disease is associated with decreased HIV but higher HBV and HCV comorbidities in U.S. hospital discharge records: a cross-sectional study. Sex Transm Infect. 2012;88(7):528-533. Kumari N, Ammosova T, Diaz S, et al. Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease. Blood Adv. 2016;1(3):170-183. Nekhai S, Xu M, Foster A, et al. Reduced sensitivity of the ferroportin Q248H mutant to physiological concentrations of hepcidin. Haematologica. 2013;98(3):455-463. Disclosures Anastos: NINR: Research Funding; NHGRI: Research Funding; NICHD: Research Funding; NIMH: Research Funding; NHLBI: Research Funding; NCI: Research Funding; NIAID: Research Funding; NINDS: Research Funding; NIDCR: Research Funding; NIMHD: Research Funding; NLM: Research Funding; Fogarty: Research Funding; NIDDK: Research Funding; NIA: Research Funding; NIAAA: Research Funding; NIDA: Research Funding.
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Tabbah, Sammy, Catalin Buhimschi, Katherine Rodewald-Millen, Christopher Pierson, Vineet Bhandari, Philip Samuels, and Irina Buhimschi. "Hepcidin, an Iron Regulatory Hormone of Innate Immunity, is Differentially Expressed in Premature Fetuses with Early-Onset Neonatal Sepsis." American Journal of Perinatology 35, no. 09 (February 2, 2018): 865–72. http://dx.doi.org/10.1055/s-0038-1626711.
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Objective Hepcidin, a mediator of innate immunity, binds the iron exporter ferroportin, leading to functional hypoferremia through intracellular iron sequestration. We explored hepcidin–ferroportin interactions in neonates clinically diagnosed with early-onset neonatal sepsis (EONS). Study Design Hepcidin and interleukin (IL)-6 were quantified by enzyme-linked immunosorbent assay (ELISA) in 92 paired cord blood–maternal blood samples in the following groups: “Yes” EONS (n = 41, gestational age [GA] 29 ± 1 weeks) and “No” EONS (n = 51, GA 26 ± 1 weeks). Placental hepcidin and ferroportin expression were evaluated by immunohistochemistry and real-time-polymerase chain reaction (RT-PCR). Liver hepcidin and ferroportin expression patterns were ascertained in autopsy specimens of neonates (n = 8) who died secondary to culture-proven sepsis. Results Cord blood hepcidin was significantly elevated (GA corrected, p = 0.018) and was positively correlated with IL-6 (r = 0.379, p = 0.001) in EONS. Hepcidin localized at syncytiotrophoblast and fetal vascular endothelium. Placental ferroportin, but not hepcidin mRNA correlated with cord blood hepcidin levels (r = 0.46, p = 0.039) and funisitis severity (r = 0.50, p = 0.018). Newborns who died from sepsis (n = 4) had higher hepatic hepcidin and iron sequestration, but lower ferroportin staining than those who died of nonsepsis causes (n = 4). Conclusion Premature fetuses with EONS have elevated circulating hepcidin, likely related to lower placenta and liver ferroportin expression. Fetal hepcidin–ferroportin interaction appears to play a role in EONS pathophysiology independent of maternal response to intrauterine inflammation.
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Sabelli, Manuela, Giuliana Montosi, Cinzia Garuti, Angela Caleffi, Stefania Oliveto, Stefano Biffo, and Antonello Pietrangelo. "Human macrophage ferroportin biology and the basis for the ferroportin disease." Hepatology 65, no. 5 (March 22, 2017): 1512–25. http://dx.doi.org/10.1002/hep.29007.
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Witcher, Derrick R., Donmienne Leung, Karen A. Hill, David C. De Rosa, Jianghuai Xu, Joseph Manetta, Victor J. Wroblewski, and Robert J. Benschop. "LY2928057, An Antibody Targeting Ferroportin, Is a Potent Inhibitor Of Hepcidin Activity and Increases Iron Mobilization In Normal Cynomolgus Monkeys." Blood 122, no. 21 (November 15, 2013): 3433. http://dx.doi.org/10.1182/blood.v122.21.3433.3433.
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Abstract Hepcidin, a 25-amino acid peptide hormone which is primarily synthesized and secreted from the liver, is a key regulator of iron homeostasis. It regulates dietary iron absorption, plasma iron concentrations, and tissue iron distribution through interactions with ferroportin, the only known mammalian cellular iron exporter. Hepcidin induces the internalization and subsequent degradation of ferroportin. The reduction in iron release caused by the loss of ferroportin, combined with the continuing demand for iron by erythropoietic precursors, results in a decrease in circulating iron levels. Dysregulation of the hepcidin-ferroportin axis contributes to the pathogenesis of different anemias. Decreased synthesis of hepcidin may cause systemic iron overload in iron-loading anemias such as beta-thalassemia; whereas overproduction of hepcidin may contribute to the development of anemia in inflammatory disorders, malignancies, and chronic kidney disease. LY2928057 is a novel humanized IgG4 monoclonal antibody that binds to human ferroportin with a high affinity, blocks the binding of human hepcidin to ferroportin, and is a potent inhibitor of hepcidin activity in a recombinant ferroportin expressing HEK 293 cell-based assay. In addition, this antibody was able to significantly inhibit hepcidin-induced increase in ferritin levels using Caco-2 cells, a human enterocyte cell line that naturally expresses ferroportin. LY2928057 does not block the efflux of iron from ferroportin, nor does this antibody cause the internalization of this transporter in vitro. Administration of LY2928057 results in a dose dependent increase in serum iron and hepcidin in normal cynomolgus monkeys. LY2928057 may provide therapeutic benefit for patients with hepcidin-related anemia by stabilizing ferroportin located on the cell surface, thus restoring iron export and erythropoiesis. LY2928057 is currently in clinical evaluation. Disclosures: Witcher: Eli Lilly and Company: Employment, Equity Ownership. Leung:Eli Lilly and Company: Employment, Equity Ownership. Hill:Eli Lilly and Company: Employment, Equity Ownership. De Rosa:Eli Lilly and Company: Employment, Equity Ownership. Xu:Eli Lilly and Company: Employment, Equity Ownership. Manetta:Eli Lilly and Company: Employment, Equity Ownership. Wroblewski:Eli Lilly and Company: Employment, Equity Ownership. Benschop:Eli Lilly and Company: Employment, Equity Ownership.
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Vlasveld, L. Tom, Roel Janssen, Edouard Bardou-Jacquet, Hanka Venselaar, Houda Hamdi-Roze, Hal Drakesmith, and Dorine W. Swinkels. "Twenty Years of Ferroportin Disease: A Review or An Update of Published Clinical, Biochemical, Molecular, and Functional Features." Pharmaceuticals 12, no. 3 (September 9, 2019): 132. http://dx.doi.org/10.3390/ph12030132.
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Iron overloading disorders linked to mutations in ferroportin have diverse phenotypes in vivo, and the effects of mutations on ferroportin in vitro range from loss of function (LOF) to gain of function (GOF) with hepcidin resistance. We reviewed 359 patients with 60 ferroportin variants. Overall, macrophage iron overload and low/normal transferrin saturation (TSAT) segregated with mutations that caused LOF, while GOF mutations were linked to high TSAT and parenchymal iron accumulation. However, the pathogenicity of individual variants is difficult to establish due to the lack of sufficiently reported data, large inter-assay variability of functional studies, and the uncertainty associated with the performance of available in silico prediction models. Since the phenotypes of hepcidin-resistant GOF variants are indistinguishable from the other types of hereditary hemochromatosis (HH), these variants may be categorized as ferroportin-associated HH, while the entity ferroportin disease may be confined to patients with LOF variants. To further improve the management of ferroportin disease, we advocate for a global registry, with standardized clinical analysis and validation of the functional tests preferably performed in human-derived enterocytic and macrophagic cell lines. Moreover, studies are warranted to unravel the definite structure of ferroportin and the indispensable residues that are essential for functionality.
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Johnson, Erin E., Andreas Sandgren, Bobby J. Cherayil, Megan Murray, and Marianne Wessling-Resnick. "Role of Ferroportin in Macrophage-Mediated Immunity." Infection and Immunity 78, no. 12 (September 13, 2010): 5099–106. http://dx.doi.org/10.1128/iai.00498-10.
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ABSTRACT Perturbations in iron metabolism have been shown to dramatically impact host response to infection. The most common inherited iron overload disorder results from defects in the HFE gene product, a major histocompatibility complex class I-like protein that interacts with transferrin receptors. HFE-associated hemochromatosis is characterized by abnormally high levels of the iron efflux protein ferroportin. In this study, J774 murine macrophages overexpressing ferroportin were used to investigate the influence of iron metabolism on the release of nitric oxide (NO) in response to infection. Overexpression of ferroportin significantly impaired intracellular Mycobacterium tuberculosis growth during early stages of infection. When challenged with lipopolysaccharide (LPS) or M. tuberculosis infection, control macrophages increased NO synthesis, but macrophages overexpressing ferroportin had significantly impaired NO production in response to LPS or M. tuberculosis. Increased NO synthesis in control cells was accompanied by increased iNOS mRNA and protein, while upregulation of iNOS protein was markedly reduced when J744 cells overexpressing ferroportin were challenged with LPS or M. tuberculosis, thus limiting the bactericidal activity of these macrophages. The proinflammatory cytokine gamma interferon reversed the inhibitory effect of ferroportin overexpression on NO production. These results suggest a novel role for ferroportin in attenuating macrophage-mediated immune responses.
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Nemeth, Elizabeta, and Tomas Ganz. "Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis." International Journal of Molecular Sciences 22, no. 12 (June 17, 2021): 6493. http://dx.doi.org/10.3390/ijms22126493.
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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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Canonne-Hergaux, François, Adriana Donovan, Constance Delaby, Hui-jun Wang, and Philippe Gros. "Comparative studies of duodenal and macrophage ferroportin proteins." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 1 (January 2006): G156—G163. http://dx.doi.org/10.1152/ajpgi.00227.2005.
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Intestinal epithelial cells and reticuloendothelial macrophages are, respectively, involved in diet iron absorption and heme iron recycling from senescent erythrocytes, two critical processes of iron homeostasis. These cells appear to use the same transporter, ferroportin (Slc40a1), to export iron. The aim of this study was to compare the localization, expression, and regulation of ferroportin in both duodenal and macrophage cells. Using a high-affinity purified polyclonal antibody, we analyzed the localization and expression of ferroportin protein in the spleen, liver, and duodenum isolated from normal mice as well as from well-characterized mouse models of altered iron homeostasis. Ferroportin was found to be predominantly expressed in enterocytes of the duodenum, in splenic macrophages, and in liver Kupffer cells. Interestingly, the protein species detected in these cells migrated differently on SDS-PAGE. These differences in apparent molecular masses were partly explained by posttranslational complex N-linked glycosylations. In addition, in enterocytes, the transporter was mostly expressed at the basolateral membrane, whereas in bone marrow-derived macrophages, ferroportin was found predominantly localized in the intracellular vesicular compartment. However, some microdomains positive for ferroportin were also detected at the plasma membrane of macrophages. Despite these differences, we observed a parallel upregulation of ferroportin expression in tissue macrophages and enterocytes in response to iron-restricted erythropoiesis, suggesting that iron homeostasis is likely maintained through coordinate expression of the iron exporter in both intestinal and phagocytic cells. Our data also confirm a predominant regulation of ferroportin through systemic regulator(s) likely including hepcidin.
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Jin, Lian, David M. Frazer, Yan Lu, Sarah J. Wilkins, Scott Ayton, Ashley Bush, and Gregory J. Anderson. "Mice overexpressing hepcidin suggest ferroportin does not play a major role in Mn homeostasis." Metallomics 11, no. 5 (2019): 959–67. http://dx.doi.org/10.1039/c8mt00370j.
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Gajewska, Joanna, Jadwiga Ambroszkiewicz, Witold Klemarczyk, Ewa Głąb-Jabłońska, Halina Weker, and Magdalena Chełchowska. "Ferroportin-Hepcidin Axis in Prepubertal Obese Children with Sufficient Daily Iron Intake." International Journal of Environmental Research and Public Health 15, no. 10 (October 1, 2018): 2156. http://dx.doi.org/10.3390/ijerph15102156.
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Iron metabolism may be disrupted in obesity, therefore, the present study assessed the iron status, especially ferroportin and hepcidin concentrations, as well as associations between the ferroportin-hepcidin axis and other iron markers in prepubertal obese children. The following were determined: serum ferroportin, hepcidin, ferritin, soluble transferrin receptor (sTfR), iron concentrations and values of hematological parameters as well as the daily dietary intake in 40 obese and 40 normal-weight children. The ferroportin/hepcidin and ferritin/hepcidin ratios were almost two-fold lower in obese children (p = 0.001; p = 0.026, respectively). Similar iron concentrations (13.2 vs. 15.2 µmol/L, p = 0.324), the sTfR/ferritin index (0.033 vs. 0.041, p = 0.384) and values of hematological parameters were found in obese and control groups, respectively. Iron daily intake in the obese children examined was consistent with recommendations. In this group, the ferroportin/hepcidin ratio positively correlated with energy intake (p = 0.012), dietary iron (p = 0.003) and vitamin B12 (p = 0.024). In the multivariate regression model an association between the ferroportin/hepcidin ratio and the sTfR/ferritin index in obese children (β = 0.399, p = 0.017) was found. These associations did not exist in the controls. The results obtained suggest that in obese children with sufficient iron intake, the altered ferroportin-hepcidin axis may occur without signs of iron deficiency or iron deficiency anemia. The role of other micronutrients, besides dietary iron, may also be considered in the iron status of these children.
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Shah, Yatrik. "Update on Ferroportin Regulation." Blood 136, Supplement 1 (November 5, 2020): SCI6. http://dx.doi.org/10.1182/blood-2020-133056.
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Parrow, Nermi L., and Robert E. Fleming. "RNF217: brokering ferroportin degradation." Blood 138, no. 8 (April 13, 2021): 593–94. http://dx.doi.org/10.1182/blood.2021011496.
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Bayele, Henry K., and Surjit Kaila S. Srai. "A disease-causing mutation K240E disrupts ferroportin trafficking by SUMO (ferroportin SUMOylation)." Biochemistry and Biophysics Reports 25 (March 2021): 100873. http://dx.doi.org/10.1016/j.bbrep.2020.100873.
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Theurl, Igor, Milan Theurl, Markus Seifert, Sabine Mair, Manfred Nairz, Holger Rumpold, Heinz Zoller, et al. "Autocrine formation of hepcidin induces iron retention in human monocytes." Blood 111, no. 4 (February 15, 2008): 2392–99. http://dx.doi.org/10.1182/blood-2007-05-090019.
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Hepcidin, a master regulator of iron homeostasis, is produced in small amounts by inflammatory monocytes/macrophages. Chronic immune activation leads to iron retention within monocytes/macrophages and the development of anemia of chronic disease (ACD). We questioned whether monocyte-derived hepcidin exerts autocrine regulation toward cellular iron metabolism. Monocyte hepcidin mRNA expression was significantly induced within 3 hours after stimulation with LPS or IL-6, and hepcidin mRNA expression was significantly higher in monocytes of ACD patients than in controls. In ACD patients, monocyte hepcidin mRNA levels were significantly correlated to serum IL-6 concentrations, and increased monocyte hepcidin mRNA levels were associated with decreased expression of the iron exporter ferroportin and iron retention in these cells. Transient transfection experiments using a ferroportin/EmGFP fusion protein construct demonstrated that LPS inducible hepcidin expression in THP-1 monocytes resulted in internalization and degradation of ferroportin. Transfection of monocytes with siRNA directed against hepcidin almost fully reversed this lipopolysaccharide-mediated effect. Using ferroportin mutation constructs, we found that ferroportin is mainly targeted by hepcidin when expressed on the cell surface. Our results suggest that ferroportin expression in inflammatory monocytes is negatively affected by autocrine formation of hepcidin, thus contributing to iron sequestration within monocytes as found in ACD.
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Nekhai, Sergei, Altreisha Foster, Min Xu, Xiaomei Niu, Jamie Rotimi, and Victor R. Gordeuk. "Inhibition of HIV-1 by Ferroprotin Expression." Blood 112, no. 11 (November 16, 2008): 1464. http://dx.doi.org/10.1182/blood.v112.11.1464.1464.
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Abstract HIV-1 transcription is induced by viral Tat protein, which recruits transcriptional co-activators to the HIV-1 promoter. We recently showed that Tat is phosphorylated in the Ser16 and Ser 46 residues by protein kinase CDK2 and that mutations in these residues prevent HIV-1 transcription and viral replication [1]. We also found that iron depletion by iron chelators inhibits cellular activity of CDK2, prevents Tat phosphorylation and inhibits HIV-1 transcription [2]. Thus our previous studies suggest that a decrease in cellular iron might have a protective effect against HIV-1 through inhibition of CDK2 and Tat phosphorylation. Here, we analyzed the effect of the iron exporter, ferroportin, on HIV-1 transcription and viral replication. Increased expression of ferroportin by transfection in iron-treated 293T cells significantly reduced ferritin protein levels compared to increased expression of CD4 or EGFP in iron-treated cells as controls. Treatment with hepcidin increased ferritin levels in 293T cells that expressed wild type ferroportin but not the C326Y mutant of ferroprotin which is not sensitive to hepcidin. Expression of both wild type ferroportin and the C326Y mutant in 293T cells significantly inhibited HIV-1 transcription. Treatment with hepcidin partially restored HIV-1 transcription in the cells expressing wild type ferroportin and not in those expressing the C326Y mutant of ferroportin. Treatment of promonocytic THP-1 cells with iron increased cellular ferritin level. Subsequent treatment with phorbol myristate acetate (PMA) led to increased expression of ferroportin and reduced ferritin level, and this reduction in ferritin was partially alleviated by exposing the cells to hepcidin. Thus, PMA appeared to reduce intracellular iron through increased iron export by ferroportin. HIV-1 replication in iron-supplemented THP-1 cells or primary human monocytes was significantly reduced by treatment with PMA. Subsequent exposure of the PMA-treated monocytes to hepcidin partially restored HIV-1 replication, suggesting that HIV-1 was inhibited in part by the expression of ferroportin and its associated iron-exporting activity. Taken together, our results indicate that expression of ferroportin leads to reduction of cellular iron and also reduced HIV-1 transcription and replication, and that exposure to hepcidin may lead to increased cellular iron content and enhancement of HIV-1 replication. Thus our results suggest that iron depletion of cells that harbor HIV might serve as a strategy to combat this infection, and they point to the need to develop iron chelators specifically designed for HIV-1 therapy.
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Huang, Dong-Liang, Jing-Si Bai, Meng Wu, Xia Wang, Bernd Riedl, Elisabeth Pook, Carsten Alt, et al. "Non-reducible disulfide bond replacement implies that disulfide exchange is not required for hepcidin–ferroportin interaction." Chemical Communications 55, no. 19 (2019): 2821–24. http://dx.doi.org/10.1039/c9cc00328b.
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Non-reducible disulfide bond replacement was used to study the disculfide exchange between hepcidin and ferroportin, and the results indicate that the hepcidin–ferroportin interaction does not require disfulfide exchange.
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Guida, Claudia, Sandro Altamura, Felix A. Klein, Bruno Galy, Michael Boutros, Artur J. Ulmer, Matthias W. Hentze, and Martina U. Muckenthaler. "A novel inflammatory pathway mediating rapid hepcidin-independent hypoferremia." Blood 125, no. 14 (April 2, 2015): 2265–75. http://dx.doi.org/10.1182/blood-2014-08-595256.
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Key PointsStimulation of Toll-like receptors 2 and 6 reduces ferroportin expression in mouse macrophages by hepcidin-independent mechanism(s). Reduced expression of ferroportin in macrophages that recycle iron from red cells is sufficient to rapidly induce hypoferremia in mice.
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Parry, Christian, Guelaguetza Vazquez-meves, Andrey Ivanov, Xionghao Lin, Namita Kumari, and Sergei Nekhai. "Structure of human ferroportin (SLC40A1) inferred from mass spectrometry restraints." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 187.35. http://dx.doi.org/10.4049/jimmunol.202.supp.187.35.
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Abstract Nearly all organisms require iron for red blood cell manufacture, respiration, metabolism and immunity, and as cofactor in several enzymes. Paradoxically, free iron is toxic from the production of reactive oxygen species which induce cellular injury and damage to DNA. It is essential that iron is tightly regulated. Ferroportin is the only known exporter of cellular iron in mammals. Its function and expression are tightly regulated by hepcidin. Carriers of ferroportin mutation Q248H show reduced sensitivity to hepcidin, have elevated iron stores and high HIV-1 viral load. In HIV-1 infection, there is marked alteration in iron balance indicated by high ferritin levels. As well, iron-regulating peptide hepcidin is greatly elevated. High iron stores correlate with high morbidity, increased opportunistic infections and faster progression to AIDS: high iron content in bone marrow macrophage parallels greater infection, immune dysfunction and poor prognosis. By contrast, other studies show that patients who were being treated for iron overload with iron chelators had delayed AIDS progression and longer survival. In spite of its importance little structural information is available on human ferroportin, and how iron is transported through ferroportin is not understood. We have built the structure of ferroportin using hybrid methods with restraints from mass spectrometry. Our model comprises 12 transmembrane helices. The iron binding site matches what is seen in crystal structures of distant orthologs. We are using this structure along with functional data to answer outstanding questions about the mechanism of ferroportin, iron transport and the importance of the Q248H mutation found in African and black American populations.
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Nemeth, Elizabeta, Gloria C. Preza, Chun-Ling Jung, Jerry Kaplan, Alan J. Waring, and Tomas Ganz. "The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study." Blood 107, no. 1 (January 1, 2006): 328–33. http://dx.doi.org/10.1182/blood-2005-05-2049.
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Abstract Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in mice by the induction of hypoferremia. Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when 5 N-terminal aa's were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin and did not interfere with ferroportin internalization by native hepcidin. Deletion of 2 C-terminal aa's did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not affect peptide activity in vitro. However, these peptides were less active in vivo, likely because of their decreased stability in circulation. G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations.
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Hawula, Zachary J., Daniel F. Wallace, V. Nathan Subramaniam, and Gautam Rishi. "Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis." Pharmaceuticals 12, no. 4 (November 25, 2019): 170. http://dx.doi.org/10.3390/ph12040170.
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The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.
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Zohn, Irene E., Ivana De Domenico, Andrew Pollock, Diane McVey Ward, Jessica F. Goodman, Xiayun Liang, Amaru J. Sanchez, Lee Niswander, and Jerry Kaplan. "The flatiron mutation in mouse ferroportin acts as a dominant negative to cause ferroportin disease." Blood 109, no. 10 (February 8, 2007): 4174–80. http://dx.doi.org/10.1182/blood-2007-01-066068.
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Abstract Ferroportin disease is caused by mutation of one allele of the iron exporter ferroportin (Fpn/IREG1/Slc40a1/MTP1). All reported human mutations are missense mutations and heterozygous null mutations in mouse Fpn do not recapitulate the human disease. Here we describe the flatiron (ffe) mouse with a missense mutation (H32R) in Fpn that affects its localization and iron export activity. Similar to human patients with classic ferroportin disease, heterozygous ffe/+ mice present with iron loading of Kupffer cells, high serum ferritin, and low transferrin saturation. In macrophages isolated from ffe/+ heterozygous mice and through the use of Fpn plasmids with the ffe mutation, we show that Fpnffe acts as a dominant negative, preventing wild-type Fpn from localizing on the cell surface and transporting iron. These results demonstrate that mutations in Fpn resulting in protein mislocalization act in a dominant-negative fashion to cause disease, and the Fpnffe mouse represents the first mouse model of ferroportin disease.
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Johnson, Erin E., and Marianne Wessling-Resnick. "Flatiron Mice and Ferroportin Disease." Nutrition Reviews 65, no. 7 (June 28, 2008): 341–45. http://dx.doi.org/10.1111/j.1753-4887.2007.tb00312.x.
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Wallace, Daniel F., Cameron J. McDonald, Lesa Ostini, David Iser, Annabel Tuckfield, and V. Nathan Subramaniam. "The dynamics of hepcidin-ferroportin internalization and consequences of a novel ferroportin disease mutation." American Journal of Hematology 92, no. 10 (July 29, 2017): 1052–61. http://dx.doi.org/10.1002/ajh.24844.
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Borges, Marina, Marina Dal'Bó Pelegrini Campioni, Dulcinéia Martins de Albuquerque, Carolina Lanaro, Fernando F. Costa, and Kleber Yotsumoto Fertrin. "Aceruloplasminemia and Paroxysmal Nocturnal Hemoglobinuria Uncover Differential Expressions of Ceruloplasmin and Ferroportin in Immune Cells." Blood 132, Supplement 1 (November 29, 2018): 4895. http://dx.doi.org/10.1182/blood-2018-99-113485.
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Abstract Ceruloplasmin (CP) is a multicopper ferroxidase that oxidizes ferrous iron promoting the binding of ferric iron to transferrin. The secreted form of CP (sCP) produced mainly by the liver is essentially absent in patients with aceruloplasminemia, a rare type of hereditary iron overload with brain, liver and pancreatic siderosis. Alternative RNA splicing generates a form of CP that is anchored by glycosylphosphatidylinositol (GPI-CP) to the membrane of astrocytes and immune cells. GPI-CP has been reported to help stabilize ferroportin, the only known iron exporter in mammal cells, so we aimed to investigate whether ferroportin expression is abnormal in circulating blood cells in aceruloplasminemia and in paroxysmal nocturnal hemoglobinuria (PNH), a naturally-occurring human model of acquired deficiency of GPI-anchored proteins. Peripheral blood samples were collected from two patients with aceruloplasminemia with different mutations on the CP gene: CP c.2879-1 G>T (splice site mutation) and CP c.2756 T>C (missense mutation), both with undetectable levels of sCP (<0.02g/L), one patient with a large PNH clone (89.9% type III), and a healthy control. Immunophenotype was determined by incubation with fluorescent antibodies against GPI-CP, ferroportin, and known lineage surface markers (CD45, CD14, CD19, and HLA-DR), data acquisition on a FACS Canto equipment, and analysis with software FACS Diva. GPI-CP and ferroportin were only detectable in CD19+ lymphocytes and monocytes in all samples. We found no significant differences across subjects regarding lymphocytic expression of GPI-CP or ferroportin. In monocytes, the expressions of both proteins in aceruloplasminemia with CP c.2879-1 G>T were similar to those seen in the control. Nevertheless, monocytic expression of GPI-CP and ferroportin were significantly reduced in CP c.2756 T>C and PNH, when compared to the control. These data confirm previous observations that B lymphocytes and monocytes express GPI-CP and ferroportin, and concomitant reduction of both expressions in PNH and in CP c.2756 T>C support that GPI-CP fosters ferroportin stability on the cell membrane. We also show that, while germline mutations of the CP gene generally cause undetectable sCP, there is heterogeneity in GPI-CP expression, which may remain preserved, as observed in CP c.2879-1 G>T. Further studies are necessary to clarify why this splice site mutation would still allow GPI-anchoring, while the CP c.2756 T>C point mutation abrogates the ability to anchor GPI-CP. While the preservation of lymphocytic GPI-CP was not surprising in an essentially myeloid PNH clone, normal GPI-CP in B lymphocytes in aceruloplasminemia suggests there are lineage-specific differences in physiological expression of ceruloplasmin forms between B lymphocytes and monocytes, with possible implications to the importance of iron metabolism in immune responses. We also noticed that the CP c.2756 T>C patient with monocytic reduction ferroportin presented with slightly more intense anemia and microcytosis. This could result from lower expression of ferroportin in bone marrow macrophages, with impaired iron delivery to erythroblasts, in analogy to monocytes. Finally, acquired ferroportin deficiency in PNH monocytes implies that loss of GPI-anchored protein not only exposes these cells to lysis by complement, but also to intracellular iron retention, generation of reactive oxygen species and may be involved in the pathophysiology of PNH. In summary, our data show that heterogeneity in GPI-CP expression in B lymphocytes and monocytes results in differential expression of ferroportin in aceruloplasminemia and PNH, and future studies should aim at investigating the implications of dysregulated iron metabolism in immune cells. Disclosures Fertrin: Apopharma Inc.: Honoraria; Alexion Pharmaceuticals Brasil: Speakers Bureau.
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Wessling-Resnick, Marianne. "Iron Imports. III. Transfer of iron from the mucosa into circulation." American Journal of Physiology-Gastrointestinal and Liver Physiology 290, no. 1 (January 2006): G1—G6. http://dx.doi.org/10.1152/ajpgi.00415.2005.
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Transfer of iron from the mucosa is a critical step in dietary iron assimilation that is tightly regulated to ensure the appropriate amount of iron is absorbed to meet the body's demands. Too much iron is highly toxic, and failure to properly control intestinal iron export causes iron overload associated with hereditary forms of hemochromatosis. One form of genetic iron overload, ferroportin disease, originates due to defects in ferroportin, the membrane iron exporter. Ferroportin acts in conjunction with the intestinal ferroxidase hephaestin to mediate release of iron from the enterocyte. How iron is then acquired by transferrin and released into circulation remains an unknown step in this process.
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Vazquez-Meves, Guelaguetza, Namita Kumari, Nowah Afangbedji, Alfia Khaibullina, Zena Quezado, Sergei Nekhai, and Marina Jerebtsova. "Upregulation of Renal Iron Metabolism in Sickle Cell Disease Mice." Blood 128, no. 22 (December 2, 2016): 1276. http://dx.doi.org/10.1182/blood.v128.22.1276.1276.
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Abstract BACKGROUND: Hemolysis and frequent blood transfusions lead to the iron overload and organ iron accumulation in patients with red blood cells disorders. The pattern of iron accumulation within different organs is disease specific. Abnormalities of renal iron metabolism and cortical iron deposition is characteristic for sickle cell disease (SCD) but not for β-thalassemia. Renal iron deposition does not correlate with iron overload and blood transfusion. Iron is reabsorbed from primary urine in the renal proximal epithelial cells and released into the renal intersitium by ferroportin. Iron-regulating hormone, hepcidin controls ferroportin expression. Binding of hepcidin to the ferroportin induces ferroportin degradation and intracellular iron accumulation. Low concentrations of circulating hepcidin are common in SCD patients and do not explain paradoxical renal iron accumulation. SCD mice accumulate iron in the epithelial cells of proximal tubules and may be a suitable model to study iron metabolism in SCD. OBJECTIVES: To characterize proteins of the renal iron metabolism in SCD mouse model. METHODS: The SCD (Townes) mice do not express mouse α- or β-globin alleles, but carry two copies of a human α1-globin gene and two copies of a human Aγ-globin and βS-globin genes. These animals synthesize approximately 94% human sickle (HbS) and 6% human fetal hemoglobin (HbF), and no murine hemoglobin. Control animals carry two copies of the human α1-globin gene and two copies of the human hemoglobin gamma (Aγ) gene and the human wildtype hemoglobin beta (βA) gene. Kidneys were collected from 5 months old SCD and control mice. Renal cortex was used for RNA and protein isolation. Levels of renal hepcidin, ferroportin, transferrin receptor (TFR1), divalent cation receptor (DMT1), ferritin and hepheastin were determined by q-RT-PCR, WB and ELISA. Paraffin-embedded sections were used for immunostaining. Perl's Prussian blue staining was used for detection of renal iron accumulation. RESULTS:We detected significant accumulation of iron in the epithelial cells of proximal tubules in SCD mice. Expression of renal hepcidin was increased in SCD mice compared to controls. Surprisingly mRNA levels of all other proteins involved in renal iron metabolism (ferroportin, TFR1, DMT1, ferritin and hephaestin) were decreased in SCD mice kidney. In contrast, we found increased protein levels of transferrin receptor (iron importer), ferritin (iron storage protein) and slightly increased level of ferroportin (iron exporter). We also observed significant renal macrophages infiltration in SCD mice. CONCLUSIONS: Increased levels of renal hepcidin expression in SCD mice may be associated with renal inflammation. Higher levels of locally expressed hepcidin may lead to the partial degradation of the iron exporter (ferroportin). Increased levels of iron importers (TFR1 and DMT1) and no significant change in ferroportin expression can cumulatively saturate iron storage in ferritin and lead to the accumulation of intracellular iron. ACKNOWLEDGMENTS: This work was supported by NIH Research Grants 1P50HL118006, 1R01HL125005 and 5G12MD007597. The content is solely the responsibility of the authors and does not necessarily represent the official view of NHLBI, NIMHD or NIH. Disclosures Quezado: IONIS Pharmaceuticals: Research Funding.
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Muckenthaler, Martina U. "The Role of Hepcidin in Health And Disease." Blood 126, no. 23 (December 3, 2015): SCI—43—SCI—43. http://dx.doi.org/10.1182/blood.v126.23.sci-43.sci-43.
Full textAbstract:
Imbalances of iron homeostasis account for some of the most common human diseases. Pathologies result from both, iron deficiency or overload and frequently affect the hepcidin/ferroportin regulatory system that balances systemic iron metabolism. The small hepatic peptide hormone hepcidin orchestrates systemic iron fluxes and controls plasma iron levels by binding to the iron exporter ferroportin on the surface of iron releasing cells, triggering its degradation and hence reducing iron transfer to transferrin. Hepcidin thus maintains transferrin saturation at physiological levels assuring adequate iron supplies to all cell types. My presentation will focus on mechanisms that control hepcidin and ferroportin expression as well as on pathologies that arise when this key regulatory circuitry underlying systemic iron homeostasis is disrupted. Disclosures No relevant conflicts of interest to declare.
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Ross, Sandra L., Lynn Tran, Aaron Winters, Ki-Jeong Lee, Cherylene Plewa, Ian Foltz, Chadwick King, et al. "Molecular Mechanism of Hepcidin-Mediated Ferroportin Internalization Requires Ferroportin Lysines, Not Tyrosines or JAK-STAT." Cell Metabolism 15, no. 6 (June 2012): 905–17. http://dx.doi.org/10.1016/j.cmet.2012.03.017.
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Ganz, Tomas. "Hepcidin and iron regulation, 10 years later." Blood 117, no. 17 (April 28, 2011): 4425–33. http://dx.doi.org/10.1182/blood-2011-01-258467.
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Abstract Under evolutionary pressure to counter the toxicity of iron and to maintain adequate iron supply for hemoglobin synthesis and essential metabolic functions, humans and other vertebrates have effective mechanisms to conserve iron and to regulate its concentration, storage, and distribution in tissues. The iron-regulatory hormone hepcidin, first described 10 years ago, and its receptor and iron channel ferroportin control the dietary absorption, storage, and tissue distribution of iron. Hepcidin causes ferroportin internalization and degradation, thereby decreasing iron transfer into blood plasma from the duodenum, from macrophages involved in recycling senescent erythrocytes, and from iron-storing hepatocytes. Hepcidin is feedback regulated by iron concentrations in plasma and the liver and by erythropoietic demand for iron. Genetic malfunctions affecting the hepcidin-ferroportin axis are a main cause of iron overload disorders but can also cause iron-restricted anemias. Modulation of hepcidin and ferroportin expression during infection and inflammation couples iron metabolism to host defense and decreases iron availability to invading pathogens. This response also restricts the iron supply to erythropoietic precursors and may cause or contribute to the anemia associated with infections and inflammatory disorders.
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Gnana-Prakasam, Jaya P., Pamela M. Martin, Barbara A. Mysona, Penny Roon, Sylvia B. Smith, and Vadivel Ganapathy. "Hepcidin expression in mouse retina and its regulation via lipopolysaccharide/Toll-like receptor-4 pathway independent of Hfe." Biochemical Journal 411, no. 1 (March 13, 2008): 79–88. http://dx.doi.org/10.1042/bj20071377.
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Hepcidin is a hormone central to the regulation of iron homeostasis in the body. It is believed to be produced exclusively by the liver. Ferroportin, an iron exporter, is the receptor for hepcidin. This transporter/receptor is expressed in Müller cells, photoreceptor cells and the RPE (retinal pigment epithelium) within the retina. Since the retina is protected by the retinal–blood barriers, we asked whether ferroportin in the retina is regulated by hepcidin in the circulation or whether the retina produces hepcidin for regulation of its own iron homeostasis. Here we show that hepcidin is expressed robustly in Müller cells, photoreceptor cells and RPE cells, closely resembling the expression pattern of ferroportin. We also show that bacterial LPS (lipopolysaccharide) is a regulator of hepcidin expression in Müller cells and the RPE, both in vitro and in vivo, and that the regulation occurs at the transcriptional level. The action of LPS on hepcidin expression is mediated by the TLR4 (Toll-like receptor-4). The upregulation of hepcidin by LPS occurs independent of Hfe (human leukocyte antigen-like protein involved in Fe homeostasis). The increase in hepcidin levels in retinal cells in response to LPS treatment is associated with a decrease in ferroportin levels. The LPS-induced upregulation of hepcidin and consequent down-regulation of ferroportin is associated with increased oxidative stress and apoptosis within the retina in vivo. We conclude that retinal iron homeostasis may be regulated in an autonomous manner by hepcidin generated within the retina and that chronic bacterial infection/inflammation of the retina may disrupt iron homeostasis and retinal function.
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Ganz, Tomas, and Elizabeta Nemeth. "The Hepcidin-Ferroportin System as a Therapeutic Target in Anemias and Iron Overload Disorders." Hematology 2011, no. 1 (December 10, 2011): 538–42. http://dx.doi.org/10.1182/asheducation-2011.1.538.
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Abstract The review summarizes the current understanding of the role of hepcidin and ferroportin in normal iron homeostasis and its disorders. The various approaches to therapeutic targeting of hepcidin and ferroportin in iron-overload disorders (mainly hereditary hemochromatosis and β-thalassemia) and iron-restrictive anemias (anemias associated with infections, inflammatory disorders, and certain malignancies, anemia of chronic kidney diseases, and iron-refractory iron-deficiency anemia) are also discussed.
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Mena, Natalia P., Andrés Esparza, Victoria Tapia, Pamela Valdés, and Marco T. Núñez. "Hepcidin inhibits apical iron uptake in intestinal cells." American Journal of Physiology-Gastrointestinal and Liver Physiology 294, no. 1 (January 2008): G192—G198. http://dx.doi.org/10.1152/ajpgi.00122.2007.
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Hepcidin (Hepc) is considered a key mediator in iron trafficking. Although the mechanism of Hepc action in macrophages is fairly well established, much less is known about its action in intestinal cells, one of the main targets of Hepc. The current study investigated the effects of physiologically generated Hepc on iron transport in Caco-2 cell monolayers and rat duodenal segments compared with the effects on the J774 macrophage cell line. Addition of Hepc to Caco-2 cells or rat duodenal segments strongly inhibited apical 55Fe uptake without apparent effects on the transfer of 55Fe from the cells to the basolateral medium. Concurrently, the levels of divalent metal transporter 1 (DMT1) mRNA and protein in Caco-2 cells decreased while the mRNA and protein levels of the iron export transporter ferroportin did not change. Plasma membrane localization of ferroportin was studied by selective biotinylation of apical and basolateral membrane domains; Hepc induced rapid internalization of ferroportin in J774 cells but not in Caco-2 cells These results indicate that the effect of Hepc is cell dependent: in macrophages it inhibits iron export by inducing ferroportin degradation, whereas in enterocytes it inhibits apical iron uptake by inhibiting DMT1 transcription. Our results highlight the crucial role of Hepc in the control of intestinal iron absorption.
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Kurtses Gürsoy, Betül, Murat İlhan Atagün, Ahmet Üzer, Adem Donukara, Halit Buğra Koca, and Ahmet Kahraman. "Iron transportation proteins Hepcidin and Ferroportin and alterations in depressive and anxiety disorders." Medical Science and Discovery 9, no. 12 (December 29, 2022): 666–71. http://dx.doi.org/10.36472/msd.v9i12.853.
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Objective: Iron element has critical roles such as myelin synthesis and neurotransmitter synthesis. Critical enzymes and proteins strictly control iron metabolism. Alterations in the enzyme activities could modify iron metabolism. Metabolic and endocrine changes may influence iron turnover in patients with major depression and anxiety disorders. Materials and Methods: 30 patients with major depressive disorder (MDD), 30 with anxiety disorders (ADs) according to the DSM 5 criteria, and 30 healthy controls were included. Hamilton Depression and Anxiety Scales were the clinical evaluation tools. Blood samples were collected 12 hours of fasting. Hepcidin and Ferroportin levels were measured with ELISA method. Results: Both Hepcidin and Ferroportin levels were lower in the MDD group compared to the ADs group, Hepcidin levels were found to be statistically significantly lower (p= 0.014). In addition, an inverse correlation was observed between the Hamilton Depression Scale score and Ferroportin levels (r= -0.214, p<0.05). Conclusion: Decreased Hepcidin and Ferroportin levels indicate metabolic effects in patients with MDD and disruption of the feedback mechanism between the two proteins. Considering the long duration of the disease in the MDD group in our study, the treatment period was also thought to be prolonged and the use of antidepressants might affect negative feedback.
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Chen, QiXing, ShengWen Song, and XiangMing Fang. "Pulmonary hepcidin protects against acute lung injury (P3345)." Journal of Immunology 190, no. 1_Supplement (May 1, 2013): 210.4. http://dx.doi.org/10.4049/jimmunol.190.supp.210.4.
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Abstract Hepcidin is a small cysteine-rich cationic peptide mainly produced by the liver, and is a principle iron regulatory hormone. Hepcidin could modulate acute inflammatory response via interaction with its receptor ferroportin. Recent studies showed that hepcidin was also expressed in tracheal epithelial cells. However, the role of this epithelia-derived hepcidin in lung inflammation remained unknown. Adenovirus-mediated hepcidin specific shRNA and a relative negative control were constructed and were administrated to mice intratracheally. Ten days later, the mice were subjected to cecal ligation and puncture to induce acute lung injury (ALI). The severity of lung injury was scored 24 hours after onset of ALI. The bacterial colony counts, white blood cell counts and total protein content in bronchoalveolar lavage fluid were also measured. Furthermore, the protein levels of ferroportin were analyzed using immunobloting. Adenovirus-mediated hepcidin specific shRNA significantly suppressed tracheal hepcidin levels ten days after administration. Interference of this epithelia-derived hepcidin increased bacterial proliferation, white blood cell counts and total protein content in bronchoalveolar lavage fluid, and thus exacerbated lung injury. However, the ferroportin levels were comparable between the two groups. Tracheal epithelia-derived hepcidin plays an important role in protecting against acute lung injury, which might function via a ferroportin-independent mechanism.