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Elizabeta Nemeth - One of the best experts on this subject based on the ideXlab platform.
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maternal Hepcidin determines embryo iron homeostasis in mice
Blood, 2020Co-Authors: Veena Sangkhae, Piotr Ruchala, Tomas Ganz, Allison L Fisher, Kristine Chua, Elizabeta NemethAbstract:Abstract Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone Hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces Hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo Hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked Hepcidin. We found that maternal, but not embryonic, Hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal Hepcidin. To establish how essential maternal Hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal Hepcidin activity by administering a Hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal Hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of Hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal Hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.
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regulation of the iron homeostatic hormone Hepcidin
Advances in Nutrition, 2017Co-Authors: Veena Sangkhae, Elizabeta NemethAbstract:Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet. Iron absorption is regulated by the hepatic peptide hormone Hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin. Important regulators of Hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. Disturbances in the regulation of Hepcidin contribute to the pathogenesis of many iron disorders: Hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused β-thalassemia, whereas overproduction of Hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia. This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of Hepcidin synthesis in the liver, a principal determinant of plasma Hepcidin concentrations.
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Hepcidin and host defense against infectious diseases
PLOS Pathogens, 2015Co-Authors: Kathryn R Michels, Elizabeta Nemeth, Tomas Ganz, Borna MehradAbstract:Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of Hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of Hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of Hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, Hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether Hepcidin exerts any iron-independent effects on host defenses.
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a competitive enzyme linked immunosorbent assay specific for murine Hepcidin 1 correlation with hepatic mrna expression in established and novel models of dysregulated iron homeostasis
Haematologica, 2015Co-Authors: Patrick Gutschow, Elizabeta Nemeth, Vaughn Ostland, Paul J Schmidt, Huiling Han, Thomas B Bartnikas, Michael A Pettiglio, Carolina Herrera, James Butler, Tomas GanzAbstract:Mice have been essential for distinguishing the role of Hepcidin in iron homeostasis. Currently, investigators monitor levels of murine hepatic Hepcidin-1 mRNA as a surrogate marker for the bioactive Hepcidin protein itself. Here, we describe and validate a competitive, enzyme-linked immunosorbent assay that quantifies Hepcidin-1 in mouse serum and urine. The assay exhibits a biologically relevant lower limit of detection, high precision, and excellent linearity and recovery. We also demonstrate correlation between serum and urine Hepcidin-1 values and validate the competitive enzyme-linked immunosorbent assay by analyzing plasma Hepcidin response of mice to physiological challenges, including iron deficiency, iron overload, acute blood loss, and inflammation. Furthermore, we analyze multiple murine genetic models of iron dysregulation, including β-thalassemia intermedia (Hbbth3/+), hereditary hemochromatosis (Hfe−/−, Hjv−/−, and Tfr2Y245X/Y245X), hypotransferrinemia (Trfhpx/hpx), heterozygous transferrin receptor 1 deficiency (Tfrc+/−) and iron refractory iron deficiency anemia (Tmprss6−/− and Tmprss6hem8/hem8). Novel compound iron metabolism mutants were also phenotypically characterized here for the first time. We demonstrate that serum Hepcidin concentrations correlate with liver Hepcidin mRNA expression, transferrin saturation and non-heme liver iron. In some circumstances, serum Hepcidin-1 more accurately predicts iron parameters than Hepcidin mRNA, and distinguishes smaller, statistically significant differences between experimental groups.
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Hepcidin induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium vibrio vulnificus
Cell Host & Microbe, 2015Co-Authors: Paul A Gulig, Victoria Gabayan, Erika V Valore, Joao Arezes, Piotr Ruchala, Grace Jung, Elizabeta Nemeth, Tomas Ganz, Yonca BulutAbstract:Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone Hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and Hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that Hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of Hepcidin agonists to Hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from Hepcidin-deficient mice support extraordinarily rapid bacterial growth and that this is inhibited in hypoferremic sera. Our findings demonstrate that Hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that Hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.
Tomas Ganz - One of the best experts on this subject based on the ideXlab platform.
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maternal Hepcidin determines embryo iron homeostasis in mice
Blood, 2020Co-Authors: Veena Sangkhae, Piotr Ruchala, Tomas Ganz, Allison L Fisher, Kristine Chua, Elizabeta NemethAbstract:Abstract Iron disorders are associated with adverse pregnancy outcomes, yet iron homeostatic mechanisms during pregnancy are poorly understood. In humans and rodents, the iron-regulatory hormone Hepcidin is profoundly decreased in pregnant mothers, which is thought to ensure adequate iron availability for transfer across placenta. However, the fetal liver also produces Hepcidin, which may regulate fetal iron endowment by controlling placental iron export. To determine the relative contribution of maternal vs embryo Hepcidin to the control of embryo iron endowment in iron-sufficient or iron-overloaded mice, we generated combinations of mothers and embryos that had or lacked Hepcidin. We found that maternal, but not embryonic, Hepcidin determined embryo and placental iron endowment in a healthy pregnancy. We further determined that inflammation can counteract pregnancy-dependent suppression of maternal Hepcidin. To establish how essential maternal Hepcidin suppression is for embryo iron homeostasis, we mimicked the range of maternal Hepcidin activity by administering a Hepcidin peptide mimetic to pregnant mice. This also allowed us to determine the effect of isolated maternal Hepcidin excess on pregnancy, in the absence of other confounding effects of inflammation. Higher doses of Hepcidin agonist caused maternal iron restriction and anemia, lower placenta and embryo weight, embryo anemia, and increased embryo mortality. Low agonist doses did not cause maternal anemia but still adversely affected the embryo, causing anemia, tissue iron deficiency (including in the brain), and decreased weight. Our studies demonstrate that suppression of maternal Hepcidin during pregnancy is essential for maternal and embryo iron homeostasis and health.
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Hepcidin and host defense against infectious diseases
PLOS Pathogens, 2015Co-Authors: Kathryn R Michels, Elizabeta Nemeth, Tomas Ganz, Borna MehradAbstract:Hepcidin is the master regulator of iron homeostasis in vertebrates. The synthesis of Hepcidin is induced by systemic iron levels and by inflammatory stimuli. While the role of Hepcidin in iron regulation is well established, its contribution to host defense is emerging as complex and multifaceted. In this review, we summarize the literature on the role of Hepcidin as a mediator of antimicrobial immunity. Hepcidin induction during infection causes depletion of extracellular iron, which is thought to be a general defense mechanism against many infections by withholding iron from invading pathogens. Conversely, by promoting iron sequestration in macrophages, Hepcidin may be detrimental to cellular defense against certain intracellular infections, although critical in vivo studies are needed to confirm this concept. It is not yet clear whether Hepcidin exerts any iron-independent effects on host defenses.
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a competitive enzyme linked immunosorbent assay specific for murine Hepcidin 1 correlation with hepatic mrna expression in established and novel models of dysregulated iron homeostasis
Haematologica, 2015Co-Authors: Patrick Gutschow, Elizabeta Nemeth, Vaughn Ostland, Paul J Schmidt, Huiling Han, Thomas B Bartnikas, Michael A Pettiglio, Carolina Herrera, James Butler, Tomas GanzAbstract:Mice have been essential for distinguishing the role of Hepcidin in iron homeostasis. Currently, investigators monitor levels of murine hepatic Hepcidin-1 mRNA as a surrogate marker for the bioactive Hepcidin protein itself. Here, we describe and validate a competitive, enzyme-linked immunosorbent assay that quantifies Hepcidin-1 in mouse serum and urine. The assay exhibits a biologically relevant lower limit of detection, high precision, and excellent linearity and recovery. We also demonstrate correlation between serum and urine Hepcidin-1 values and validate the competitive enzyme-linked immunosorbent assay by analyzing plasma Hepcidin response of mice to physiological challenges, including iron deficiency, iron overload, acute blood loss, and inflammation. Furthermore, we analyze multiple murine genetic models of iron dysregulation, including β-thalassemia intermedia (Hbbth3/+), hereditary hemochromatosis (Hfe−/−, Hjv−/−, and Tfr2Y245X/Y245X), hypotransferrinemia (Trfhpx/hpx), heterozygous transferrin receptor 1 deficiency (Tfrc+/−) and iron refractory iron deficiency anemia (Tmprss6−/− and Tmprss6hem8/hem8). Novel compound iron metabolism mutants were also phenotypically characterized here for the first time. We demonstrate that serum Hepcidin concentrations correlate with liver Hepcidin mRNA expression, transferrin saturation and non-heme liver iron. In some circumstances, serum Hepcidin-1 more accurately predicts iron parameters than Hepcidin mRNA, and distinguishes smaller, statistically significant differences between experimental groups.
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Hepcidin induced hypoferremia is a critical host defense mechanism against the siderophilic bacterium vibrio vulnificus
Cell Host & Microbe, 2015Co-Authors: Paul A Gulig, Victoria Gabayan, Erika V Valore, Joao Arezes, Piotr Ruchala, Grace Jung, Elizabeta Nemeth, Tomas Ganz, Yonca BulutAbstract:Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone Hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and Hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that Hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of Hepcidin agonists to Hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from Hepcidin-deficient mice support extraordinarily rapid bacterial growth and that this is inhibited in hypoferremic sera. Our findings demonstrate that Hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that Hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.
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cellular catabolism of the iron regulatory peptide hormone Hepcidin
PLOS ONE, 2013Co-Authors: Gloria C Preza, Tomas Ganz, Rogelio Pinon, Elizabeta NemethAbstract:Hepcidin, a 25-amino acid peptide hormone, is the principal regulator of plasma iron concentrations. Hepcidin binding to its receptor, the iron exporter ferroportin, induces ferroportin internalization and degradation, thus blocking iron efflux from cells into plasma. The aim of this study was to characterize the fate of Hepcidin after binding to ferroportin. We show that Hepcidin is taken up by ferroportin-expressing cells in a temperature- and pH-dependent manner, and degraded together with its receptor. When Texas red-labeled Hepcidin (TR-Hep) was added to ferroportin-GFP (Fpn-GFP) expressing cells, confocal microscopy showed co-localization of TR-Hep with Fpn-GFP. Using flow cytometry, we showed that the peptide was almost completely degraded by 24 h after its addition, but that lysosomal inhibitors completely prevented degradation of both ferroportin and Hepcidin. In addition, using radio-labeled Hepcidin and HPLC analysis we show that Hepcidin is not recycled, and that only degradation products are released from the cells. Together these results show that the hormone Hepcidin and its receptor ferroportin are internalized together and trafficked to lysosomes where both are degraded.
Jamie Marie Marranca - One of the best experts on this subject based on the ideXlab platform.
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identification of centrarchid Hepcidins and evidence that 17β estradiol disrupts constitutive expression of Hepcidin 1 and inducible expression of Hepcidin 2 in largemouth bass micropterus salmoides
Fish & Shellfish Immunology, 2009Co-Authors: Laura S Robertson, Luke R. Iwanowicz, Jamie Marie MarrancaAbstract:Hepcidin is a highly conserved antimicrobial peptide and iron-regulatory hormone. Here, we identify two Hepcidin genes (hep-1 and hep-2) in largemouth bass (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Hepcidin-1 contains a putative ATCUN metal-binding site in the amino-terminus that is missing in Hepcidin-2, suggesting that Hepcidin-1 may function as an iron-regulatory hormone. Both Hepcidins are predominately expressed in the liver of largemouth bass, similar to other fish and mammals. Experimental exposure of pond-raised largemouth bass to 17β-estradiol and/or the bacteria Edwardsiella ictaluri led to distinct changes in expression of hep-1 and hep-2. Estradiol reduced the constitutive expression of hep-1 in the liver. Bacterial exposure induced expression of hep-2, suggesting that Hepcidin-2 may have an antimicrobial function, and this induction was abolished by estradiol. To our knowledge, this is the first report of the regulation of Hepcidin expression by estradiol in either fish or mammals.
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identification of centrarchid Hepcidins and evidence that 17β estradiol disrupts constitutive expression of Hepcidin 1 and inducible expression of Hepcidin 2 in largemouth bass micropterus salmoides
Fish & Shellfish Immunology, 2009Co-Authors: Laura S Robertson, Luke R. Iwanowicz, Jamie Marie MarrancaAbstract:Hepcidin is a highly conserved antimicrobial peptide and iron-regulatory hormone. Here, we identify two Hepcidin genes (hep-1 and hep-2) in largemouth bass (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Hepcidin-1 contains a putative ATCUN metal-binding site in the amino-terminus that is missing in Hepcidin-2, suggesting that Hepcidin-1 may function as an iron-regulatory hormone. Both Hepcidins are predominately expressed in the liver of largemouth bass, similar to other fish and mammals. Experimental exposure of pond-raised largemouth bass to 17beta-estradiol and/or the bacteria Edwardsiella ictaluri led to distinct changes in expression of hep-1 and hep-2. Estradiol reduced the constitutive expression of hep-1 in the liver. Bacterial exposure induced expression of hep-2, suggesting that Hepcidin-2 may have an antimicrobial function, and this induction was abolished by estradiol. To our knowledge, this is the first report of the regulation of Hepcidin expression by estradiol in either fish or mammals.
Ernest Beutler - One of the best experts on this subject based on the ideXlab platform.
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regulation of Hepcidin and iron overload disease
Annual Review of Pathology-mechanisms of Disease, 2009Co-Authors: Pauline Lee, Ernest BeutlerAbstract:Hepcidin, a 25-amino-acid antimicrobial peptide, is the central regulator of iron homeostasis. Hepcidin transcription is upregulated by inflammatory cytokines, iron, and bone morphogenetic proteins and is downregulated by iron deficiency, ineffective erythropoiesis, and hypoxia. The iron transporter ferroportin is the cognate receptor of Hepcidin and is destroyed as a result of interaction with the peptide. Except for inherited defects of ferroportin and Hepcidin itself, all forms of iron-storage disease appear to arise from Hepcidin dysregulation. Studies using multiple approaches have begun to delineate the molecular mechanisms that regulate Hepcidin expression, particularly at the transcriptional level. Knowledge of the regulation of Hepcidin by inflammation, iron, erythropoiesis, and hypoxia will lead to an understanding of the pathogenesis of primary hemochromatosis, secondary iron overload, and anemia of inflammatory disease.
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regulation of Hepcidin transcription by interleukin 1 and interleukin 6
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Pauline Lee, Hongfan Peng, Terri Gelbart, Lei Wang, Ernest BeutlerAbstract:Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates Hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6-/-) respond to endotoxin by increasing the expression of Hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1alpha, and IL-1beta strongly stimulates Hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-beta inhibits transcription of Hepcidin. All of the Hepcidin stimulatory activity of macrophages from IL-6-/- mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6-/- mice, hfe-/- mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating Hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of Hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of Hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating Hepcidin.
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regulation of Hepcidin transcription by interleukin 1 and interleukin 6
Proceedings of the National Academy of Sciences of the United States of America, 2005Co-Authors: Hongfan Peng, Terri Gelbart, Lei Wang, Ernest BeutlerAbstract:Hepcidin is a peptide that regulates iron homeostasis by inhibiting iron absorption by the small intestine and release of iron from macrophages. Its production is stimulated by iron overload and by inflammation. It has been suggested that IL-6 is the only cytokine that stimulates Hepcidin transcription. However, mice with targeted disruption of the gene encoding IL-6 (IL-6–/–) respond to endotoxin by increasing the expression of Hepcidin transcripts in the liver. We show that incubating murine hepatocytes with IL-6, IL-1α, and IL-1β strongly stimulates Hepcidin transcription. IL-10 has little or no stimulatory effect, and IFN-β inhibits transcription of Hepcidin. All of the Hepcidin stimulatory activity of macrophages from IL-6–/– mice can be accounted for by IL-1 that they secrete. Hepatocytes from IL-6–/– mice, hfe–/– mice, and mice with a hypomorphic transferrin receptor 2 mutation responded to IL-6 and IL-1 by up-regulating Hepcidin transcription. Nitric oxide does not seem to be involved in the stimulation of Hepcidin transcription by cytokines: aminoguanidine does not inhibit the stimulation of Hepcidin transcription by cytokines. IL-1 may play a significant role in the anemia of inflammation by up-regulating Hepcidin.
Laura S Robertson - One of the best experts on this subject based on the ideXlab platform.
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identification of centrarchid Hepcidins and evidence that 17β estradiol disrupts constitutive expression of Hepcidin 1 and inducible expression of Hepcidin 2 in largemouth bass micropterus salmoides
Fish & Shellfish Immunology, 2009Co-Authors: Laura S Robertson, Luke R. Iwanowicz, Jamie Marie MarrancaAbstract:Hepcidin is a highly conserved antimicrobial peptide and iron-regulatory hormone. Here, we identify two Hepcidin genes (hep-1 and hep-2) in largemouth bass (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Hepcidin-1 contains a putative ATCUN metal-binding site in the amino-terminus that is missing in Hepcidin-2, suggesting that Hepcidin-1 may function as an iron-regulatory hormone. Both Hepcidins are predominately expressed in the liver of largemouth bass, similar to other fish and mammals. Experimental exposure of pond-raised largemouth bass to 17β-estradiol and/or the bacteria Edwardsiella ictaluri led to distinct changes in expression of hep-1 and hep-2. Estradiol reduced the constitutive expression of hep-1 in the liver. Bacterial exposure induced expression of hep-2, suggesting that Hepcidin-2 may have an antimicrobial function, and this induction was abolished by estradiol. To our knowledge, this is the first report of the regulation of Hepcidin expression by estradiol in either fish or mammals.
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identification of centrarchid Hepcidins and evidence that 17β estradiol disrupts constitutive expression of Hepcidin 1 and inducible expression of Hepcidin 2 in largemouth bass micropterus salmoides
Fish & Shellfish Immunology, 2009Co-Authors: Laura S Robertson, Luke R. Iwanowicz, Jamie Marie MarrancaAbstract:Hepcidin is a highly conserved antimicrobial peptide and iron-regulatory hormone. Here, we identify two Hepcidin genes (hep-1 and hep-2) in largemouth bass (Micropterus salmoides) and smallmouth bass (Micropterus dolomieu). Hepcidin-1 contains a putative ATCUN metal-binding site in the amino-terminus that is missing in Hepcidin-2, suggesting that Hepcidin-1 may function as an iron-regulatory hormone. Both Hepcidins are predominately expressed in the liver of largemouth bass, similar to other fish and mammals. Experimental exposure of pond-raised largemouth bass to 17beta-estradiol and/or the bacteria Edwardsiella ictaluri led to distinct changes in expression of hep-1 and hep-2. Estradiol reduced the constitutive expression of hep-1 in the liver. Bacterial exposure induced expression of hep-2, suggesting that Hepcidin-2 may have an antimicrobial function, and this induction was abolished by estradiol. To our knowledge, this is the first report of the regulation of Hepcidin expression by estradiol in either fish or mammals.