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1
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.
Анотація:
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.
2
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.
Анотація:
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.
3
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.
Анотація:
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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Liu, Xiao-Bing, Funmei Yang, and David J. Haile. "Functional consequences of ferroportin 1 mutations." Blood Cells, Molecules, and Diseases 35, no. 1 (July 2005): 33–46. http://dx.doi.org/10.1016/j.bcmd.2005.04.005.
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Harada, Nobuhiko, Masaya Kanayama, Atsushi Maruyama, Aruto Yoshida, Kyoko Tazumi, Tomonori Hosoya, Junsei Mimura, et al. "Nrf2 regulates ferroportin 1-mediated iron efflux and counteracts lipopolysaccharide-induced ferroportin 1 mRNA suppression in macrophages." Archives of Biochemistry and Biophysics 508, no. 1 (April 2011): 101–9. http://dx.doi.org/10.1016/j.abb.2011.02.001.
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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.
Анотація:
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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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.
Анотація:
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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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.
Анотація:
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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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.
Анотація:
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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Nekhai, Sergei A., Namita Kumari, Denitra Breuer, Charlee Mclean, Tatiana Ammosova та Subhash Dhawan. "Induction Of Ferroportin, Erg-1, p21 and IKBα In Sickle Cell Disease May Contribute To HIV-1 Inhibition". Blood 122, № 21 (15 листопада 2013): 2250. http://dx.doi.org/10.1182/blood.v122.21.2250.2250.
Анотація:
Abstract Background Hypoxia and low iron induce hypoxia-induced factor 1(HIF-1) by stabilizing its alpha subunit and deregulate HIV-1 which transcription and several other steps of life cycle depend on cellular iron [1]. HIV-1 transcription is inhibited at low oxygen levels and reduced cellular iron through deregulation of CDK9/cyclin T1 and CDK2/cyclin E. Sickle cell disease has low odds of ratio for HIV-1 infection [2]. Sickle cell disease (SCD) leads to hemolytic anemia which results in local ischemia and release of heme. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1 [1], although the mechanism of the inhibition was not clarified. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibits CDK2 and CDK9 activities and blocks HIV-1 transcription [1]. Because neither CDK2 nor CDK9 require iron for the enzymatic activity, we analyzed the expression of hypoxia and iron –dependent factors that may deregulate HIV-1 infection in SCD. Results Expression profiling followed by real-time PCR analysis showed induction of HO-1, p21, Erg-1, IKBα, HIF-1 and ferroportin mRNA and decrease of hepcidin mRNA in PBMCs from SCD patients. HIV-1 replication was reduced in SCD PBMCs comparing to normal controls, and also in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication in SCD PBMC and in hemin-treated THP-1 cells, suggesting that ferroportin played a key role in the HIV-1 inhibition in these settings. Stable ferroportin knock down in THP-1 cells led to the inability of hemin to inhibit HIV-1, suggesting that ferroportin played a key role in the heme-meidated HIV-1 inhibition. Stable HIF-1a knockdown in promonocytic THP1 cells increased HIV replication suggesting that HIF1α is a restriction factor for HIV-1. Iron chelators induced the expression of IKBα, an inhibitor of NF-kB and also induced the expression of HIF-1 and p21. Iron chelators also inhibited enzymatic activity of CDK2 and shifted CDK9/cyclin T1 from the large to the small complex making it unavailable for HIV-1 Tat recruitment. Hemin treatment induced expression of HO-1, ferroportin, IkBα, HIF1α and p21 thus mimicking the effect of iron chelators. Conclusions Hemolytic conditions of sickle cell disease upregulate hypoxia and iron regulatory pathways leading to refraction of HIV-1. Targeting cellular iron, ferroportin and HO-1 may lead to novel anti-HIV-1 therapeutics. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. References 1. Nekhai S, Kumari N, Dhawan S: Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 2013, 8(3):301-311. 2. 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. Disclosures: No relevant conflicts of interest to declare.
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Xu, Min, Fatah Kashanchi, Altreisha Foster, Jamie Rotimi, Willie Turner, Victor R. Gordeuk, and Sergei Nekhai. "Hepcidin induces HIV-1 transcription inhibited by ferroportin." Retrovirology 7, no. 1 (2010): 104. http://dx.doi.org/10.1186/1742-4690-7-104.
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Starzyński, Rafał R., François Canonne-Hergaux, Małgorzata Lenartowicz, Wojciech Krzeptowski, Alexandra Willemetz, Agnieszka Styś, Joanna Bierła, Piotr Pietrzak, Tomasz Dziaman, and Paweł Lipiński. "Ferroportin expression in haem oxygenase 1-deficient mice." Biochemical Journal 449, no. 1 (December 7, 2012): 69–78. http://dx.doi.org/10.1042/bj20121139.
Анотація:
HO1 (haem oxygenase 1) and Fpn (ferroportin) are key proteins for iron recycling from senescent red blood cells and therefore play a major role in controlling the bioavailability of iron for erythropoiesis. Although important aspects of iron metabolism in HO1-deficient (Hmox1−/−) mice have already been revealed, little is known about the regulation of Fpn expression and its role in HO1 deficiency. In the present study, we characterize the cellular and systemic factors influencing Fpn expression in Hmox1−/− bone marrow-derived macrophages and in the liver and kidney of Hmox1−/− mice. In Hmox1−/− macrophages, Fpn protein was relatively highly expressed under high levels of hepcidin in culture medium. Similarly, despite high hepatic hepcidin expression, Fpn is still detected in Kupffer cells and is also markedly enhanced at the basolateral membrane of the renal tubules of Hmox1−/− mice. Through the activity of highly expressed Fpn, epithelial cells of the renal tubules probably take over the function of impaired system of tissue macrophages in recycling iron accumulated in the kidney. Moreover, although we have found increased expression of FLVCR (feline leukaemia virus subgroup C receptor), a haem exporter, in the kidneys of Hmox1−/− mice, haem level was increased in these organs. Furthermore, we show that iron/haem-mediated toxicity are responsible for renal injury documented in the kidneys of Hmox1−/− mice.
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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.
Анотація:
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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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.
Анотація:
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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Kumari, Namita, Tatiana Ammosova, and Sergei Nekhai. "Heme Oxygenase-1, Ferroportin and SAMHD1 Induction By Heme Inhibits HIV-1." Blood 126, no. 23 (December 3, 2015): 3359. http://dx.doi.org/10.1182/blood.v126.23.3359.3359.
Анотація:
Abstract Background Heme oxygenase-1 (HO-1) induction by hemin inhibitsHIV-1 infection in cultured macrophages and T-cells and also in HIV-1 infected humanized mice via a protein kinase C-dependent pathway (reviewed in [1]). LPS-treated human macrophages express HO-1 which may protect them against HIV-1 infection through the production of MIP1α, MIP1β and LD78β chemokines that decrease CCR5 expression. Iron depletion by iron chelators or through the expression of ferroportin, an iron export protein, inhibited HIV-1 [2, 3]. Objective We analyzed the effect of heme on HIV-1 infection in macrophages and the contribution of heme and iron regulatory proteins including HO-1, ferroportin and hepcidin and cell cycle regulatory cell cycle dependent kinase 2 (CDK2) and p21, which are deregulated by iron depletion. We also analyzed SAM domain and HD domain-containing protein 1 (SAMHD1) as it was shown to be regulated by CDK2 and p21. Methods One round HIV-1 infection was analyzed in THP-1 cells infected with VSVg-pseudotyped HIV-1 expressing luciferase. Gene expression and protein expression analysis was carried out using RNA and protein isolated from hemin treated and untreated cells using RT PCR western blot respectively. Specific gene knock-downswere generated in THP-1 cells using lentivirus expressing gene-targeted shRNAs. Results In heme-treated THP-1 cells, mRNA expression of ferroportin, p21, SAMHD1, hypoxia-induced factor (HIF)-1α, and IKBα and NF-κB inhibitor was increased and CDK2 expression decreased. Stable ferroportin knock-down prevented HIV-1 inhibition in THP-1 cells. Treatment with hepcidin also restored HIV-1 inhibition in hemin treated THP-1 cells. Ferritin levels increased in Hemin treated THP1 cells and decreased when cells were treated with tin protoporphyrin (SnPP) IX inaddtion to hemin, suggesting that HO-1 induction leads to intracellular iron accumulation. In addition, hemin treatment reduced the expression of p65 subunit of NF-kB and induced expression of NF-κB inhibitor, IKBα. We also observed increased expression of p21 and decreased expression of CDK2 in the cells treated with hemin and accumulation of the cells in the G1 phase of the cell cycle. Both CDK2 and p21 control phosphorylation of SAMHD1 which in turn controls the dNTP pool and prevents HIV-1 reverse transcription. We observed reduced expression of CDK2 and increased expression of SAMHD1 and p21 in hemin treated cells, which may also contribute to the inhibition of HIV-1. Stable HIF-1a knockdown in THP-1 cells increased HIV-1 replication indicating that HIF-1a might also restrict HIV-1 replication. Conclusion Our study shows that induction of HIF-1a and iron export and utilization proteins protects hemin-treated THP-1 cells from HIV-1 infection. Block of HIV-1 inhibition by heme in THP-1 cells with stable ferroportin knock-down and restoration of HIV-1 replication with hepcidin in heme-treated THP-1 cells suggest that ferroportin plays a key role in the HIV-1 inhibition. Additional molecular mechanisms of heme-mediated HIV-1 inhibition might also include NF-kB inhibition by IKBα, reduction of CDK2 expression and induction of SAMHD1 and p21. Thus this complex deregulation of iron metabolism leads to the inhibition of HIV-1 transcription. Acknowledgments This work was supported by NIH Research Grants (1P50HL118006, 1R01HL125005, U19AI109664 and 5G12MD007597) and District of Columbia Developmental Center for AIDS Research grant (1P30AI117970). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. References 1. Nekhai S, Kumari N, Dhawan S: Role of cellular iron and oxygen in the regulation of HIV-1 infection. Future Virol 2013, 8(3):301-311. 2. Kumari N, Iordanskiy S, Kovalskyy D, Breuer D, Niu X, Lin X, Xu M, Gavrilenko K, Kashanchi F, Dhawan S et al: Phenyl-1-Pyridin-2yl-ethanone-based iron chelators increase IkappaB-alpha expression, modulate CDK2 and CDK9 activities, and inhibit HIV-1 transcription. Antimicrob Agents Chemother 2014, 58(11):6558-6571. 3. Xu M, Kashanchi F, Foster A, Rotimi J, Turner W, Gordeuk VR, Nekhai S: Hepcidin induces HIV-1 transcription inhibited by ferroportin. Retrovirology 2010, 7:104. Disclosures No relevant conflicts of interest to declare.
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Troadec, Marie-Berengere, Diane McVey Ward, Eric Lo, Jerry Kaplan, and Ivana De Domenico. "Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux." Blood 116, no. 22 (November 25, 2010): 4657–64. http://dx.doi.org/10.1182/blood-2010-04-278614.
Анотація:
Ferroportin (Fpn) is the only known iron exporter in vertebrate cells and plays a critical role in iron homeostasis regulating cytosolic iron levels and exporting iron to plasma. Ferroportin1 (FPN1) expression can be transcriptionally regulated by iron as well as other transition metals. Fpn can also be posttranslationally regulated by hepcidin-mediated internalization and degradation. We demonstrate that zinc and cadmium induce FPN1 transcription through the action of Metal Transcription Factor-1 (MTF-1). These transition metals induce MTF-1 translocation into the nucleus. Zinc leads to MTF-1 binding to the FPN1 promoter, while iron does not. Silencing of MTF-1 reduces FPN1 transcription in response to zinc but not in response to iron. The mouse FPN1 promoter contains 2 MTF-1 binding sites and mutation of those sites affects the zinc and cadmium-dependent expression of a FPN1 promoter reporter construct. We demonstrate that Fpn can transport zinc and can protect zinc sensitive cells from high zinc toxicity.
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LIU, Weidong, Souji SHIMOMURA, Hiroyasu IMANISHI, Yuna IWAMOTO, Naoto IKEDA, Masaki SAITO, Masao OHNO, et al. "Hemochromatosis with Mutation of the Ferroportin 1 (IREG1) Gene." Internal Medicine 44, no. 4 (2005): 285–89. http://dx.doi.org/10.2169/internalmedicine.44.285.
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Chung, Jayong, Joseph R. Prohaska, and Marianne Wessling-Resnick. "Ferroportin-1 Is Not Upregulated in Copper-Deficient Mice." Journal of Nutrition 134, no. 3 (March 1, 2004): 517–21. http://dx.doi.org/10.1093/jn/134.3.517.
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Iacovelli, Jared, Agnieska E. Mlodnicka, Peter Veldman, Gui-Shuang Ying, Joshua L. Dunaief, and Armin Schumacher. "Brain and retinal ferroportin 1 dysregulation in polycythaemia mice." Brain Research 1289 (September 2009): 85–95. http://dx.doi.org/10.1016/j.brainres.2009.06.098.
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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.
Анотація:
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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Kumari, Namita, Tatiana Ammosova, Sharmin Diaz, Xionghao Lin, Xiaomei Niu, Andrey Ivanov, Marina Jerebtsova, Subhash Dhawan, Patricia Oneal, and Sergei Nekhai. "Increased iron export by ferroportin induces restriction of HIV-1 infection in sickle cell disease." Blood Advances 1, no. 3 (December 14, 2016): 170–83. http://dx.doi.org/10.1182/bloodadvances.2016000745.
Анотація:
Key PointsFerroportin reduces intracellular iron, inhibits CDK2 and suppresses SAMHD1 phosphorylation thus inhibiting HIV-1 RT. Ferroportin expression leads to overexpression of IKBα and inhibition of HIV-1 transcription.
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Xu, Youjia, Wei Zhang, Peng Zhang, Li Xiao, Aidong Wang, Pierre Sirois, and Kai Li. "Downregulation of Ferroportin 1 Expression in hFOB1.19 Osteoblasts by Hepcidin." Inflammation 35, no. 3 (January 14, 2012): 1058–61. http://dx.doi.org/10.1007/s10753-011-9411-8.
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Abdullah, Md, Donghee Lee, Rong Li, and Jong Hyuk Kim. "Abstract 4459: Metabolic liabilities of iron-dependent ferroptosis mediated through NRF2/GPX4 axis in osteosarcoma." Cancer Research 84, no. 6_Supplement (March 22, 2024): 4459. http://dx.doi.org/10.1158/1538-7445.am2024-4459.
Анотація:
Abstract Osteosarcoma is an aggressive bone malignancy that predominantly affects adolescents and young adults. Despite recent advancements in treatments, the challenges of recurrence and chemoresistance persist. Ferroptosis is a form of regulated cell death driven by iron-dependent lipid peroxidation, and emerging evidence suggests significant roles for NRF2 and GPX4 in iron metabolism, regulating tumor cell functions. In osteosarcoma, however, the molecular mechanisms of the NRF2/GPX4 axis and its therapeutic potential remain unknown. In this study, we first determined GPX4 and xCT expression levels and cellular responses to RSL3, a GPX4 inhibitor, and Erastin, an xCT inhibitor in osteosarcoma cells. A total of seven osteosarcoma cell lines, consisting of five human cell lines (HOS, 143B, Saos-2, MG-63, U2OS) and two canine cell lines (COS31 and DOUG), were used. Our results revealed that the IC50 values ranged from 0.02 uM to 1.01 uM in cells treated with RSL3 and from 0.35 uM to 1.41 uM in cells treated with Erastin, respectively. These values were proportional to GPX4 and xCT levels across the cell lines. Then, U2OS, as the most sensitive, and Saos-2, the least sensitive based on their IC50 values, were selected to examine the iron regulatory machinery. In U2OS cells, RSL3 treatment significantly decreased NRF2 and GPX4, while increasing ferroportin-1 and ferritin. GPX4 knockdown also led to comparable changes in NRF2, ferroportin-1, and ferritin expression. NRF2 appears to mediate iron metabolism, ferroportin-1 acts as an iron exporter, and ferritin stores intracellular iron. Therefore, our findings suggest that GPX4-mediated ferroptosis is regulated by iron metabolic pathways, potentially to prevent ferroptotic cell death. We also found that Ferrostatin-1, a lipid peroxidation inhibitor showed no changes in ferroportin-1, ferritin, and NRF2. In Saos-2, RSL3 induced a remarkable reduction in GPX4 expression, akin to U2OS. However, no significant change was found in NRF2, ferroportin-1, and ferritin. Instead, Ferrostatin-1 restored the decreased GPX4 and increased NRF2, ferroportin-1, and ferritin levels. In addition, Z-VAD (a pan-caspase inhibitor), Necrosatin-1s (a RIPK1 inhibitor), and Ferrostatin-1 were capable of preventing Saos-2, COS31, and DOUG cells from RSL3-induced cell death at lethal doses. Such protection was undetected in U2OS. These data suggest that metabolic pathways controlling intracellular iron are crucial for NRF2/GPX4-mediated ferroptosis in osteosarcoma cells. Furthermore, we generated RNA-seq and LC-MS/MS data to identify novel molecular targets governing the metabolic pathways of ferroptosis in osteosarcoma. Our ongoing work includes downstream molecular and functional assays following gene modifications in osteosarcoma cells (overexpression and knockout) and assessing metabolic vulnerabilities by targeting iron-mediated ferroptosis in xenografts. Citation Format: Md Abdullah, Donghee Lee, Rong Li, Jong Hyuk Kim. Metabolic liabilities of iron-dependent ferroptosis mediated through NRF2/GPX4 axis in osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4459.
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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.
Анотація:
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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Zhang, An-Sheng, Shigang Xiong, Hidekazu Tsukamoto, and Caroline A. Enns. "Localization of iron metabolism–related mRNAs in rat liver indicate that HFE is expressed predominantly in hepatocytes." Blood 103, no. 4 (February 15, 2004): 1509–14. http://dx.doi.org/10.1182/blood-2003-07-2378.
Анотація:
Abstract The mRNAs of proteins involved in iron metabolism were measured in isolated hepatocytes, Kupffer cells, sinusoidal endothelial cells (SECs), and hepatic stellate cells (HSCs). Levels of type I hereditary hemochromatosis gene (HFE), transferrin, hepcidin, transferrin receptors 1 and 2 (TfR1, TfR2), ferroportin 1 (FPN1), divalent metal transporter 1 (DMT1), natural resistance–associated macrophage protein 1 (Nramp1), ceruloplasmin, hephaestin, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), were measured by quantitative reverse-transriptase polyerase chain reaction (qRT-PCR). We show that hepatocytes express almost all the iron-related genes tested, in keeping with their central role in iron metabolism. In addition, hepatocytes had 10-fold lower TfR1 mRNA levels than TfR2 and the lowest levels of TfR1 of the 4 cell types isolated. Kupffer cells, which process senescent red blood cells and recycle the iron, had high levels of ferroportin 1, ceruloplasmin, and hephaestin mRNA. Most important, of all the cell types tested, hepatocytes had the highest level of HFE mRNA, a factor of 10 higher than Kupffer cells. In situ hybridization analysis was conducted with rat liver sections. Consistent with the qRT-PCR analysis, HFE gene expression was localized mainly in hepatocytes. Western blot analysis confirmed this finding. Unexpectedly, HSCs also had high levels of DMT1 and ferroportin, implicating them in either iron sensing or iron cycling.
26
Sakamoto, Shinji, Mika Kirinashizawa, Yumi Mohara, and Yoshihiro Watanabe. "Generation and characterization of monoclonal antibodies against mature hepcidin and its application to neutralization and quantitative alteration assay." Bioscience, Biotechnology, and Biochemistry 85, no. 2 (January 20, 2021): 340–50. http://dx.doi.org/10.1093/bbb/zbaa013.
Анотація:
ABSTRACTHepcidin regulates the quantity of ferroportin (FPN) on cellular membrane. In our cell assay expressing ferroportin labeled with green fluorescence, FPN was internalized and degraded only after treatment with hepcidin-25, not hepcidin-22 or hepcidin-20, leading to accumulation of cellular iron. Thus we generated murine monoclonal antibodies (mAbs) against hepcidin-25, and then characterized and validated their functions. Among them, several mAbs showed a neutralizing activity that may prevent ferroportin internalization induced by hepcidin-25. To measure hepcidin level in various fluids, mAbs specific for human and rat hepcidin-25 were selected. As for rat, a sandwich ELISA developed using clone rHN1 as capture antibody and biotinylated clone mHW1 as a detection reagent had high sensitivity, allowing for the detection of 1-100 ng/mL of hepcidin-25. Rat hepcidin-25 level in plasma was measured at an average concentration of 63.0 ng/mL in healthy condition, and at 218.2 ng/mL after stimulation of lipopolysaccharide.
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Papanikolaou, George, Michalis Tzilianos, John I. Christakis, Dionisios Bogdanos, Konstantina Tsimirika, Julie MacFarlane, Y. Paul Goldberg, Nikos Sakellaropoulos, Tomas Ganz, and Elizabeta Nemeth. "Hepcidin in iron overload disorders." Blood 105, no. 10 (May 15, 2005): 4103–5. http://dx.doi.org/10.1182/blood-2004-12-4844.
Анотація:
Abstract Hepcidin is the principal regulator of iron absorption in humans. The peptide inhibits cellular iron efflux by binding to the iron export channel ferroportin and inducing its internalization and degradation. Either hepcidin deficiency or alterations in its target, ferroportin, would be expected to result in dysregulated iron absorption, tissue maldistribution of iron, and iron overload. Indeed, hepcidin deficiency has been reported in hereditary hemochromatosis and attributed to mutations in HFE, transferrin receptor 2, hemojuvelin, and the hepcidin gene itself. We measured urinary hepcidin in patients with other genetic causes of iron overload. Hepcidin was found to be suppressed in patients with thalassemia syndromes and congenital dyserythropoietic anemia type 1 and was undetectable in patients with juvenile hemochromatosis with HAMP mutations. Of interest, urine hepcidin levels were significantly elevated in 2 patients with hemochromatosis type 4. These findings extend the spectrum of iron disorders with hepcidin deficiency and underscore the critical importance of the hepcidin–ferroportin interaction in iron homeostasis.
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Repo, Marleena, Markus Hannula, Juha Taavela, Jari Hyttinen, Jorma Isola, Pauliina Hiltunen, Alina Popp, Katri Kaukinen, Kalle Kurppa, and Katri Lindfors. "Iron Transporter Protein Expressions in Children with Celiac Disease." Nutrients 13, no. 3 (February 27, 2021): 776. http://dx.doi.org/10.3390/nu13030776.
Анотація:
Anemia is a frequent finding in children with celiac disease but the detailed pathophysiological mechanisms in the intestine remain obscure. One possible explanation could be an abnormal expression of duodenal iron transport proteins. However, the results have so far been inconsistent. We investigated this issue by comparing immunohistochemical stainings of duodenal cytochrome B (DCYTB), divalent metal transporter 1 (DMT1), ferroportin, hephaestin and transferrin receptor 1 (TfR1) in duodenal biopsies between 27 children with celiac disease and duodenal atrophy, 10 celiac autoantibody-positive children with potential celiac disease and six autoantibody-negative control children. Twenty out of these 43 subjects had anemia. The expressions of the iron proteins were investigated with regard to saturation and the percentage of the stained area or stained membrane length of the enterocytes. The results showed the stained area of ferroportin to be increased and the saturation of hephaestin to be decreased in celiac disease patients compared with controls. There were no differences in the transporter protein expressions between anemic and non-anemic patients. The present results suggest an iron status-independent alteration of ferroportin and hephaestin proteins in children with histologically confirmed celiac disease.
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M. Ali, Zahra, Shatha H. Ali, and Forat Y. Mohsen. "Assessment of Some Hematological parameters in Iraqi Women with Different Breast Cancer Stages." Iraqi Journal of Pharmaceutical Sciences ( P-ISSN: 1683 - 3597 , E-ISSN : 2521 - 3512) 29, no. 2 (December 27, 2020): 99–106. http://dx.doi.org/10.31351/vol29iss2pp99-106.
Анотація:
Breast cancer (BC) is the most commonly diagnosed cancer in women. The metabolism of iron is closely regulated by hepcidin which exerts its action by interacting with a ferroportin.
The aim of the present study was to assess the alterations in the levels of some serum biomarkers that have a role in iron homeostasis (hepcidin and ferroportin) in addition to hematological parameters (hemoglobin, leukocyte and platelets count) in different stages of BC.
This study included 66 women with BC. The patients were categorized as follows : group 1 includes :22 patients with stage I disease ,group 2 includes: 22 patients with stage II disease ,and group 3 include: 22 patients with stage III disease .Group 4 includes :22 apparently healthy women as control.
Data analysis revealed a significant elevation of serum hepcidin levels of patients groups 1, 2, and 3 (437.2±26.4, 501.4±31.8 and 558.5±21.3 pg/ml respectively) ,vs (179.4±19.8 pg/ml) of control, with steady elevations from stage I to III . Furthermore, serum ferroportin levels were significantly lowered in groups 1 and 3 compared to control (0.589±0.107 and 0.733±0.1 vs 1.37±0.28 ng/ml respectively).While blood hemoglobin level of group 3 were lower (11.96±0.18 vs 12.7±0.13g/dl ) compared with controls . Blood leukocyte count of patients (all groups) (7.39±0.28 ,8.93±0.48,9.86±0.52 (^103/µl) respectively) were markedly increased compared to controls (6.06±0.23), while mean platelet count for patients in group 2&3 were significantly increased compared to controls (313.9±19.3,309.2±25.3 vs 233.3±9.1 respectively).
In conclusion, hepcidin, ferroportin and hematological markers including hemoglobin, WBC count and platelets count are altered in women with BC compared to healthy control. The changes occur mostly in accordance with disease stages.
30
Park, Bo-Yoen, and Jayong Chung. "Effect of Copper on the Regulation of Ferroportin-1 Gene Expression." Korean Journal of Nutrition 42, no. 5 (2009): 434. http://dx.doi.org/10.4163/kjn.2009.42.5.434.
31
Beutler, Ernest, James C. Barton, Vincent J. Felitti, Terri Gelbart, Carol West, Pauline L. Lee, Jill Waalen, and Chris Vulpe. "Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans." Blood Cells, Molecules, and Diseases 31, no. 3 (November 2003): 305–9. http://dx.doi.org/10.1016/s1079-9796(03)00165-7.
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Mok, H. "Dysregulation of ferroportin 1 interferes with spleen organogenesis in polycythaemia mice." Development 131, no. 19 (October 1, 2004): 4871–81. http://dx.doi.org/10.1242/dev.01342.
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McGregor, J. A., M. Shayeghi, C. D. Vulpe, G. J. Anderson, A. Pietrangelo, R. J. Simpson, and A. T. Mckie. "Impaired Iron Transport Activity of Ferroportin 1 in Hereditary Iron Overload." Journal of Membrane Biology 206, no. 1 (July 2005): 3–7. http://dx.doi.org/10.1007/s00232-005-0768-1.
34
Lin, Qing, Junsheng Feng, Xiaozhen Zhao, Geng Zhang, and Wei Wang. "Expression and Function of Ferroportin 1 in O-2A Progenitor Cells." Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology 296, no. 1 (November 1, 2012): 108–16. http://dx.doi.org/10.1002/ar.22610.
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Ronzoni, Luisa, Alessandra Colancecco, Laura Sonzogni, Giovanna Graziadei, and Maria Domenica Cappellini. "In Vitro Ferroportin Expression in Thalassemia Intermedia During Erythroid Differentiation." Blood 118, no. 21 (November 18, 2011): 5287. http://dx.doi.org/10.1182/blood.v118.21.5287.5287.
Анотація:
Abstract Abstract 5287 INTRODUCTION: Ferroportin (FPN) is the sole mammalian iron exporter protein known and it plays a critical role in iron metabolism. It is expressed in various types of cells including duodenal enterocytes, hepatocytes, erythroblasts cells, syncytiotrophoblasts and reticuloendothelial macrophages. Ferroportin is expressed in multiple alternative transcripts: with (FPN1A) or without (FPN1B) an iron-responsive element (IRE). The expression of one form rather than the other depends on cell type and iron availability. The expression of ferroportin in thalassemia intermedia (TI), characterized by iron overload, is not yet fully elucidated. AIM: To investigate the different expression profile of ferroportin isoforms during erythroid differentiation in control and TI cell cultures. METHODS: After informed consent, the CD34+ cells were obtained from peripheral blood of healthy volunteers and from patients with thalassemia intermedia by positive selection using anti-CD34-tagged magnetic beads and cultured for 14 days with a medium containing stem cell factor (SCF), interleukin 3 (IL-3) and erythropoietin to induce erythroid differentiation. The expression profiling of FPN1A and FPN1B was evaluated at baseline, day 7 and day 14 of culture by real-time PCR (2̂-dCt). RESULTS: In control cultures, FPN1A isoform was highly expressed at erythroid progenitors stage (day 0 of culture), decreased at early erythroblasts stage (day 7) and increased again at late erythroblasts stage (day 14). In TI cultures, the FPN1A isoform expression remained high even in early erythroblasts (Table 1). In control cultures the FPN1B isoform expression was very low at any stage of erythroid differentiation, whereas in TI cultures it was highly expressed at baseline and, althoug decreased during differentiation, remained always higher than control (Table 2). CONCLUSIONS: In thalassemic conditions the FPN1B is the major expressed ferroportin isoform, possibly contributing to iron overload. In control cultures, FPN1A was mainly expressed in undifferentiated erythroid progenitors and in mature erythroblasts, suggesting a functional role at these stages of erythroid differentiation. In TI cultures, the persistent expression of FPN1A at early erythroblasts stage was probably due to thalassemic erythropoiesis. These data suggest that in TI condition other signals, such as the erythropoiesis status, can override iron overload in regulating ferroportin expression. Disclosures: No relevant conflicts of interest to declare.
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Viprakasit, Vip, Alison T. Merryweather-Clarke, Yingyong Chinthammitr, Lisa Schimanski, Hal Drakesmith, Somdet Srichairatanakool, Chanin Limwongse, Alain Townsend, and Kathryn J. H. Robson. "Molecular Diagnosis of the First Ferroportin Mutation (C326Y) in the Far East Causing a Dominant Form of Inherited Iron Overload." Blood 104, no. 11 (November 16, 2004): 3204. http://dx.doi.org/10.1182/blood.v104.11.3204.3204.
Анотація:
Abstract Genetic hemochromatosis (HH) is a common inherited disorder in populations of European origin in which different types of genetic hemochromatosis (type 1–4) have been characterized. Most hemochromatosis-type 1 patients are homozygotes or compound heterozygotes for two HFE mutations C282Y and H63D. Studies of several non-HFE iron overload families led to identification of mutations in hemojuvelin and hepcidin (juvenile form-HFE2A and B), transferrin receptor 2 (HFE3) and ferroportin (HFE4) as a cause of different forms of hemochromatosis. In the Far East, inherited hemochromatosis has rarely been reported and may have been misdiagnosed due to the high prevalence of secondary iron loading from hemoglobin disorders. This report describes, for the first time, non-HFE iron overload in patients from Southeast Asia. The affected Thai family presented with a distinctive clinical phenotype including macrocytosis and elevated transferrin saturation (>95%), increased non-transferrin bound iron (NTBI) as well as raised serum ferritin and marked hepatic hemochromatosis. Our patients tolerated therapeutic phlebotomy well. DNAs from peripheral blood leukocytes were firstly analyzed for three common HFE mutations (C282Y, H63D and IVS5+1 G→A). Subsequently, we screened all coding sequences, promoters and exon/intron boundaries of the HFE, HAMP, TfR2, HJV and SLC40A1 genes using denaturing high performance liquid chromatography (DHPLC). The entire coding region and splice sites of these genes were amplified and directly sequenced. We identified a novel mutation (C326Y) in ferroportin (SLC40A1, IREG-1, MTP-1), a membrane iron transport protein due to a G→A substitution at nucleotide 1281 in exon 7. This mutation was confirmed by restriction fragment length polymorphism (RFLP) analysis using Sfa NI. Six hundred Thai and two hundred Vietnamese chromosomes were analyzed for the C326Y mutation by RFLP analysis and it was not detected in any of the healthy controls studied. This result suggested that the G→A substitution is not a common polymorphism and is likely to be the causative mutation for the phenotype in this family. Previous reported mutations of ferroportin, including A77D and V162del, which lead to type IV hemochromatosis, were characterized by increased serum ferritin despite normal transferrin saturation, in contrast to our patients’ phenotype. These autosomal dominant mutants are postulated to lead to disease due to loss of iron exporting function. Preliminary in vivo assay using transient transfection of wild-type and ferroportin mutants in HeLa or 293T cells revealed, as expected, a loss of function and diminished surface membrane localisation in A77D and V162del mutants. Surprisingly, the C326Y mutant was indistinguishable from wt ferroportin in both iron status of the cell and protein localization suggesting different pathophysiology leading to iron overload in our patients.
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Zhang, Meng-Wan, Guang Yang, Yu-Fu Zhou, Christopher Qian, Ming-Dao Mu, Ya Ke, and Zhong-Ming Qian. "Regulating ferroportin-1 and transferrin receptor-1 expression: A novel function of hydrogen sulfide." Journal of Cellular Physiology 234, no. 4 (October 28, 2018): 3158–69. http://dx.doi.org/10.1002/jcp.27431.
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Devalia, Vinod, Kymberley Carter, Ann P. Walker, Stephen J. Perkins, Mark Worwood, Alison May, and James S. Dooley. "Autosomal dominant reticuloendothelial iron overload associated with a 3–base pair deletion in the ferroportin 1 gene(SLC11A3)." Blood 100, no. 2 (July 15, 2002): 695–97. http://dx.doi.org/10.1182/blood-2001-11-0132.
Анотація:
Abstract We describe a family with autosomal dominant inheritance of increased body iron stores characterized by raised serum ferritin concentration and normal transferrin saturation. Liver biopsy showed iron deposition in Kupffer cells without fibrosis. The clinical features of HFE-related hemochromatosis were absent, as were the Cys282Tyr and His63Asp mutations. Venesection therapy was poorly tolerated, suggesting a defect in iron release from reticuloendothelial stores. A 3–base pair deletion in exon 5 of the ferroportin 1 gene (SLC11A3) predicting Val162 deletion was found in affected members, but not in unaffected individuals or in 100 control subjects. Consensus structural predictions of the transmembrane helices showed that the deletion is in the extracellular loop between the third and fourth predicted transmembrane helices and lies within a spatial cluster of other known ferroportin 1 mutations. These results indicate that this extracellular cluster is functionally important for iron transport, and its disruption leads to iron overload.
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Matak, Pavle, Andrija Matak, Sarah Moustafa, Dipendra K. Aryal, Eric J. Benner, William Wetsel, and Nancy C. Andrews. "Disrupted iron homeostasis causes dopaminergic neurodegeneration in mice." Proceedings of the National Academy of Sciences 113, no. 13 (February 29, 2016): 3428–35. http://dx.doi.org/10.1073/pnas.1519473113.
Анотація:
Disrupted brain iron homeostasis is a common feature of neurodegenerative disease. To begin to understand how neuronal iron handling might be involved, we focused on dopaminergic neurons and asked how inactivation of transport proteins affected iron homeostasis in vivo in mice. Loss of the cellular iron exporter, ferroportin, had no apparent consequences. However, loss of transferrin receptor 1, involved in iron uptake, caused neuronal iron deficiency, age-progressive degeneration of a subset of dopaminergic neurons, and motor deficits. There was gradual depletion of dopaminergic projections in the striatum followed by death of dopaminergic neurons in the substantia nigra. Damaged mitochondria accumulated, and gene expression signatures indicated attempted axonal regeneration, a metabolic switch to glycolysis, oxidative stress, and the unfolded protein response. We demonstrate that loss of transferrin receptor 1, but not loss of ferroportin, can cause neurodegeneration in a subset of dopaminergic neurons in mice.
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Knutson, Mitchell D., Mohammad R. Vafa, David J. Haile, and Marianne Wessling-Resnick. "Iron loading and erythrophagocytosis increase ferroportin 1 (FPN1) expression in J774 macrophages." Blood 102, no. 12 (December 1, 2003): 4191–97. http://dx.doi.org/10.1182/blood-2003-04-1250.
Анотація:
Abstract The expression of ferroportin1 (FPN1) in reticuloendothelial macrophages supports the hypothesis that this iron-export protein participates in iron recycling from senescent erythrocytes. To gain insight into FPN1's role in macrophage iron metabolism, we examined the effect of iron status and erythrophagocytosis on FPN1 expression in J774 macrophages. Northern analysis indicated that FPN1 mRNA levels decreased with iron depletion and increased on iron loading. The iron-induced induction of FPN1 mRNA was blocked by actinomycin D, suggesting that transcriptional control was responsible for this effect. After erythrophagocytosis, FPN1 mRNA levels were also up-regulated, increasing 8-fold after 4 hours and returning to basal levels by 16 hours. Western analysis indicated corresponding increases in FPN1 protein levels, with maximal induction after 10 hours. Iron chelation suppressed FPN1 mRNA and protein induction after erythrophagocytosis, suggesting that FPN1 induction results from erythrocyte-derived iron. Comparative Northern analyses of iron-related genes after erythrophagocytosis revealed a 16-fold increase in FPN1 levels after 3 hours, a 10-fold increase in heme oxygenase-1 (HO-1) after 3 hours, a 2-fold increase in natural resistance macrophage-associated protein 1 (Nramp1) levels after 6 hours, but no change in divalent metal ion transporter 1 (DMT1) levels. The rapid and strong induction of FPN1 expression after erythrophagocytosis suggests that FPN1 plays a role in iron recycling. (Blood. 2003;102:4191-4197)
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Valenti, L., M. Guido, P. Dongiovanni, L. Cremonesi, A. L. Fracanzani, and S. Fargion. "Ferroportin-1 in the recurrence of hepatic iron overload after liver transplantation." Digestive and Liver Disease 41, no. 7 (July 2009): e17-e20. http://dx.doi.org/10.1016/j.dld.2008.01.020.
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Kumari, Namita, та Sergei A. Nekhai. "Heme and Iron Chelators Inhibit HIV-1 Through The Induction Of Heme Oxygenase 1, Ferroportin and IKBα". Blood 122, № 21 (15 листопада 2013): 2198. http://dx.doi.org/10.1182/blood.v122.21.2198.2198.
Анотація:
Abstract Background Recently, HIV-1 infection was shown to be efficiently inhibited in macrophages and T-cells treated with hemin that was added extracellularly 1,2. Hemin administration to humanized transgenic mice significantly reduced HIV-1 viral load 1. Suppression of HIV-1 by hemin was mediated through the induction of (HO-1)1, via a protein kinase C-dependent pathway2. The inhibitory effect of hemin could be reversed by protoporphyrin, an HO-1 inhibitor 2. Induction of heme oxygenase-1 (HO-1) by hemin was shown to inhibit HIV-1. We recently analyzed the role of HO-1 in protecting LPS-treated human macrophages against HIV-1 infection3. LPS-treated macrophages were negative for mature virions, expressed HO-1 and produced MIP1α, MIP1β and LD78β chemokines which led to a decreased CCR5 expression. Treatment with HO-1 inhibitor SnPP IX (tin protoporphyrin IX) increased HIV-1 replication and decreased secretion of MIP1α, MIP1β, and LD78β chemokines. HO-1 also affects several proteins involved in cell cycle progression, and cell cycle is critical for HIV-1 progression. Hypoxia leads to induction and stabilization of HIF-1α and is inhibitory to HIV-1 replication. NF-kB is important for basal and Tat-activated HIV-1 transcription. Here we analyzed factors involved in HIV-1 transcription affected by HO-1 expression. Results HIV-1 replication was reduced in THP1 cells treated with hemin. Subsequent treatment with hepcidin restored HIV-1 replication, suggesting that ferroportin plays a key role in the HIV-1 inhibition. Stable ferroportin knock down in THP1 cells led to the inability of hemin to inhibit HIV-1, again suggesting that ferroportin plays a key role in this process. In hemin-treated THP-1 cells, expression of p21, HIF-1α and IKBα mRNA was induced. The expression of IKBα, an inhibitor of NF-kB, reduced the level of p65 subunit of NF-kB. We obtained similar results in THP-1 cell treated with iron chelators, which also induced the expression of IKBα, HIF-1 and p21. THP-1 cells treated with hemin or iron chelators were arrested in G1 phase of cell cycle. Stable HIF-1a knockdown in promonocytic THP-1 cells increased HIV replication suggesting that HIF-1 might be a restriction factor for HIV-1. In contrast to iron chelators that inhibited enzymatic activity of CDK2 without affecting its protein level, hemin treatment reduced CDK2 expression at mRNA and protein levels. Conclusions Induction of HIF-1 regulatory pathway and iron export by ferroportin might protect hemin-treated THP-1 cells from HIV-1 infection. Additional molecular mechanisms of heme-mediated HIV-1 inhibition might also include NF-kB inhibition by IKBα and CDK2 inhibition leading to the inhibition of HIV-1 transcription. Our results point to novel therapeutics, such as the use of hemin and iron chelators, both of which are FDA approved for treatment for acute porphyries and iron overload. Acknowledgments This project was supported by NIH Research Grants 1SC1GM082325, 2G12RR003048, and P30HL107253. Literature 1. Devadas K, Dhawan S. Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction. J Immunol. 2006;176(7):4252-4257. 2. Devadas K, Hewlett IK, Dhawan S. Lipopolysaccharide suppresses HIV-1 replication in human monocytes by protein kinase C-dependent heme oxygenase-1 induction. J Leukoc Biol. 2010;87(5):915-924. 3. Zhou ZH, Kumari N, Nekhai S, et al. Heme oxygenase-1 induction alters chemokine regulation and ameliorates human immunodeficiency virus-type-1 infection in lipopolysaccharide-stimulated macrophages. Biochem Biophys Res Commun. 2013;435(3):373-377. Disclosures: No relevant conflicts of interest to declare.
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Rivera, Seth, Elizabeta Nemeth, Victoria Gabayan, Miguel A. Lopez, Dina Farshidi, and Tomas Ganz. "Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs." Blood 106, no. 6 (September 15, 2005): 2196–99. http://dx.doi.org/10.1182/blood-2005-04-1766.
Анотація:
Abstract Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-μg dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50-μg dose was 1.4 μM, consistent with the inhibitory concentration of 50% (IC50) of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis. (Blood. 2005;106:2196-2199)
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Hetet, Gilles, Isabelle Devaux, Nadem Soufir, Bernard Grandchamp, and Carole Beaumont. "Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations." Blood 102, no. 5 (September 1, 2003): 1904–10. http://dx.doi.org/10.1182/blood-2003-02-0439.
Анотація:
AbstractUnexplained hyperferritinemia is a common clinical finding, even in asymptomatic persons. When early onset bilateral cataracts are also present, the hereditary hyperferritinemia-cataract syndrome (HHCS), because of heterozygous point mutation in the L ferritin iron-responsive element (IRE) sequence, can be suspected. We sequenced the L ferritin exon 1 in 52 DNA samples from patients referred to us for molecular diagnosis of HHCS. We identified 24 samples with a point mutation/deletion in the IRE. For the 28 samples in which no IRE mutation was present, we also genotyped HFE mutations and sequenced both H ferritin and ferroportin genes. We found an increased frequency of His63Asp heterozygotes (12 of 28) but no H ferritin mutations. We identified 3 new ferroportin mutations, producing, respectively, Asp157Gly, Gln182His, and Gly323Val amino acid replacements, suggesting that these patients have dominant type 4 hemochromatosis. This study demonstrates that both L ferritin IRE and ferroportin mutations can account for isolated hyperferritinemia. The presence of cataract does not permit the unambiguous identification of patients with HHCS, although the existence of a family history of cataract was only encountered in these patients. This raises the intriguing possibility that lens ferritin accumulation might be a factor contributing to age-related cataract in the general population. Additional causes of isolated hyperferritinemia remain to be identified.
45
Ahmad, Asrar, Namita Kumari, Nowah Afangbedji, Sergei Nekhai, and Marina Jerebtsova. "Induction of Hepcidin Expression in the Renal Cortex of Sickle Cell Disease Mice." International Journal of Molecular Sciences 24, no. 13 (June 28, 2023): 10806. http://dx.doi.org/10.3390/ijms241310806.
Анотація:
In patients with sickle cell disease (SCD), chronic hemolysis and frequent blood transfusions cause iron overload and accumulation in the kidneys. The iron deposition is found in the renal cortex and correlates with the severity of hemolysis. In this study, we observed a significant accumulation of iron in the renal cortex of a mouse model of SCD, and assessed the expression of the proteins involved in maintaining renal iron homeostasis. Despite the intracellular iron accumulation, the levels of the transferrin receptor in the kidneys were increased, but the levels of the iron exporter ferroportin were not altered in SCD mice. Ferroportin is regulated by hepcidin, which binds to it and promotes its degradation. We found reduced serum hepcidin levels but increased renal hepcidin production in SCD mice. Furthermore, we observed significant macrophage infiltration and increased expression of intercellular adhesion molecule 1 in the endothelial cells of the kidneys in SCD mice. These observations correlated with elevated levels of proinflammatory cytokines IL-1β and IL-6, which can potentially stimulate hepcidin expression. Taken together, our results demonstrate that in individuals with SCD, a renal inflammation state induces renal hepcidin production that blocks the upregulation of ferroportin levels, resulting in dysregulation of iron homeostasis in the kidney and iron deposition in the renal cortex.
46
Dassanayake, Praveen S. B., Rahil Prajapati, Neil Gelman, R. Terry Thompson, Frank S. Prato, and Donna E. Goldhawk. "Monocyte MRI Relaxation Rates Are Regulated by Extracellular Iron and Hepcidin." International Journal of Molecular Sciences 24, no. 4 (February 17, 2023): 4036. http://dx.doi.org/10.3390/ijms24044036.
Анотація:
Many chronic inflammatory conditions are mediated by an increase in the number of monocytes in peripheral circulation, differentiation of monocytes to macrophages, and different macrophage subpopulations during pro- and anti-inflammatory stages of tissue injury. When hepcidin secretion is stimulated during inflammation, the iron export protein ferroportin is targeted for degradation on a limited number of cell types, including monocytes and macrophages. Such changes in monocyte iron metabolism raise the possibility of non-invasively tracking the activity of these immune cells using magnetic resonance imaging (MRI). We hypothesized that hepcidin-mediated changes in monocyte iron regulation influence both cellular iron content and MRI relaxation rates. In response to varying conditions of extracellular iron supplementation, ferroportin protein levels in human THP-1 monocytes decreased two- to eightfold, consistent with paracrine/autocrine regulation of iron export. Following hepcidin treatment, ferroportin protein levels further decreased two- to fourfold. This was accompanied by an approximately twofold increase in total transverse relaxation rate, R2*, compared to non-supplemented cells. A positive correlation between total cellular iron content and R2* improved from moderate to strong in the presence of hepcidin. These findings suggest that hepcidin-mediated changes detected in monocytes using MRI could be valuable for in vivo cell tracking of inflammatory responses.
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Bair, Steven, Emily Spaulding, Jaakko Parkkinen, Howard M. Shulman, Vladimir Lesnikov, Mary Beauchamp, François Canonne-Hergaux, Kris V. Kowdley, and H. Joachim Deeg. "Transplantation of allogeneic T cells alters iron homeostasis in NOD/SCID mice." Blood 113, no. 8 (February 19, 2009): 1841–44. http://dx.doi.org/10.1182/blood-2008-09-178517.
Анотація:
AbstractIron overload is common in patients undergoing allogeneic hematopoietic cell transplantation (HCT), but the mechanisms leading to overload are unknown. Here, we determined iron levels and the expression of iron regulatory proteins in the liver and gut of nonobese diabetic–severe combined immunodeficient (NOD/SCID) mice that underwent transplantation with syngeneic (histocompatible) or allogeneic (histoincompatible) T lymphocytes. Infusion of histoincompatible T cells resulted in a significant rise in serum iron levels and liver iron content. Iron deposition was accompanied by hepatocyte injury and intestinal villous damage. Feeding of low- or high-iron diet was associated with appropriate ferroportin 1 and hepcidin responses in mice given histocompatible T cells, whereas mice given histoincompatible T cells showed inappropriate up-regulation of duodenal ferroportin 1 and a loss of expression of hepatic hepcidin. These findings suggest that alloreactive T cell–dependent signals induced dysregulation of intestinal iron absorption, which contributed to liver iron overload after HCT.
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Uguen, Kevin, Chandran Ka, Gwenaelle Collod-Béroud, Marlène Le Tertre, Julie Guellec, Claude Férec, Christophe Béroud, Isabelle Callebaut, and Gérald Le Gac. "The Spectra of Disease-Causing Mutations in the Ferroportin 1 (SLC40A1) Encoding Gene and Related Iron Overload Phenotypes (Hemochromatosis Type 4 and Ferroportin Disease)." Human Mutation 2023 (June 13, 2023): 1–22. http://dx.doi.org/10.1155/2023/5162256.
Анотація:
SLC40A1 is the sole iron export protein reported in mammals and is a key player in both cellular and systemic iron homeostasis. This unique iron exporter, which belongs to the major facilitator superfamily, is predominantly regulated by the hyposideremic hormone hepcidin. SLC40A1 dysfunction causes ferroportin disease, and autosomal dominant iron overload disorder characterized by cellular iron retention, principally in reticuloendothelial cells, correlating with high serum ferritin and low to normal transferrin saturation. Resistant to hepcidin, SLC40A1 mutations are rather associated with elevated plasma iron and parenchymal iron deposition, a condition that resembles HFE-related hemochromatosis and is associated with more clinical complications. With very few exceptions, only missense variations are reported at the SLC40A1 locus; this situation increasingly limits the establishment of pathogenicity. In this mutation update, we provide a comprehensive review of all the pathogenic or likely pathogenic variants, variants of unknown significance, and benign or likely benign SLC40A1 variants. The classification is essentially determined using functional, structural, segregation, and recurrence data. We furnish new information on genotype-phenotype correlations for loss-of-function, gain-of-function, and other SLC40A1 variants, confirming the existence of wide clinical heterogeneity and the potential for misdiagnosis. All information is recorded in a locus-specific online database.
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Martin, J., A. Aksan, D. Steinhilber, S. Ulrich-Rückert, and J. M. Stein. "P038 Targeting the hepcidin-ferroportin axis with Nrf2 agonists to treat iron deficiency anaemia in Inflammatory Bowel Disease." Journal of Crohn's and Colitis 16, Supplement_1 (January 1, 2022): i155—i156. http://dx.doi.org/10.1093/ecco-jcc/jjab232.167.
Анотація:
Abstract Background Anaemia of inflammation is a common extraintestinal manifestation of IBD, impacting patient quality of life and hospitalisation rates. High circulating levels of proinflammatory cytokines induce hepatic production of the iron-regulatory peptide hormone hepcidin. By binding to the iron exporter ferroportin, hepcidin induces its internalisation and degradation, restricting the bioavailability and absorption of iron. This study aimed to test the effect of dimethyl fumarate (DMF) and sulforaphane (SFN), known activators of the transcription factor Nrf2, on the hepcidin-ferroportin (hep-fer) axis. Methods HepG2 cells were cultivated under standard conditions and treated with DMF or SFN for 16h. For reporter gene assays, plasmids were transfected by lipofection; luciferase activity was measured luminometrically. Quantitative real-time PCR was performed to determine mRNA expression. Proteins were detected by Western blot or LC-MS/MS. For gene knockdown, HepG2 cells were transfected with targeting or nontargeting siRNA duplexes. Graph Pad Prism v.7.00 and IBM SPSS 25 were used for statistical analysis. Results Both DMF and SFN reduced basic hepcidin expression and counteracted cytokine-induced hepcidin expression at promoter, mRNA and protein levels in HepG2 cells, independent of Nrf2 activation. Furthermore, DMF caused upregulation of ferroportin and ferritin at mRNA level, dependent on induction of Nrf2 and its downstream target haem oxygenase-1 (HO-1). Conclusion The Nrf2 agonists DMF and SFN might ameliorate anaemia of inflammation by disrupting the hep-fer axis by Nrf2-dependent and -independent mechanisms, and may be a promising therapeutic option for anaemia of inflammation for patients with IBD.
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Boumaiza, Mohamed, Imene Fhoula, Fernando Carmona, Maura Poli, Michela Asperti, Alessandra Gianoncelli, Michela Bertuzzi, Paolo Arosio, and Mohamed Nejib Marzouki. "Biochemical, Biophysical and Functional Characterization of an Insoluble Iron Containing Hepcidin–Ferritin Chimeric Monomer Assembled Together with Human Ferritin H/L Chains at Different Molar Ratios." Current Issues in Molecular Biology 44, no. 1 (December 28, 2021): 117–27. http://dx.doi.org/10.3390/cimb44010009.
Анотація:
Hepcidin and ferritin are key proteins of iron homeostasis in mammals. In this study, we characterize a chimera by fusing camel hepcidin to a human ferritin H-chain to verify if it retained the properties of the two proteins. The construct (HepcH) is expressed in E. coli in an insoluble and iron-containing form. To characterize it, the product was incubated with ascorbic acid and TCEP to reduce and solubilize the iron, which was quantified with ferrozine. HepcH bound approximately five times more iron than the wild type human ferritin, due to the presence of the hepcidin moiety. To obtain a soluble and stable product, the chimera was denatured and renatured together with different amounts of L-ferritin of the H-chain in order to produce 24-shell heteropolymers with different subunit proportions. They were analyzed by denaturing and non-denaturing PAGE and by mass spectroscopy. At the 1:5 ratio of HepcH to H- or L-ferritin, a stable and soluble molecule was obtained. Its biological activity was verified by its ability to both bind specifically cell lines that express ferroportin and to promote ferroportin degradation. This chimeric molecule showed the ability to bind both mouse J774 macrophage cells, as well as human HepG2 cells, via the hepcidin–ferroportin axis. We conclude that the chimera retains the properties of both hepcidin and ferritin and might be exploited for drug delivery.