The Molecular Signature of Iron Metabolism in Polycythaemia Mice.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3579-3579
Author(s):  
Armin Schumacher ◽  
Henry Mok ◽  
Agnieszka E. Mlodnicka ◽  
Matthias W. Hentze ◽  
Martina Muckenthaler
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Transcription Initiation ◽  
Positional Cloning ◽  
Iron Homeostasis ◽  
Iron Bioavailability ◽  
Molecular Signature ◽  
Dynamic Changes ◽  
Anemia Of Chronic Disease

Abstract Recent positional cloning of the radiation-induced polycythaemia (Pcm) mutation revealed a 58-bp microdeletion in the promoter region of ferroportin 1 (Fpn1), the sole cellular iron exporter identified to date. The microdeletion causes aberrant transcription initiation and results in the absence of the iron-responsive element in the 5′ untranslated region of the vast majority of Fpn1 transcripts, thereby disrupting translational regulation of Fpn1 expression. Pcm mutant mice exhibit the gamut of iron balance disorders, ranging from iron deficiency at birth to tissue iron overload by young adulthood. Consistent with the perinatal iron deficiency, Pcm pups display a microcytic, hypochromic anemia. Strikingly, the majority of young adult Pcm heterozygous animals display a transient erythropoietin (Epo)-dependent polycythemia with peak hematocrits of up to 80%, eponymous of the mutant strain. Here we report a molecular definition of the regulatory mechanisms governing the dynamic changes in iron balance in Pcm heterozygous mice between 3 and 12 weeks of age. Therein, hepatic and/or duodenal response patterns of iron transporters, such as Trfr, cybrd1 and Slc11a2, defined the transition from early postnatal iron deficiency to iron overload by 12 weeks of age. A significant delay in developmental upregulation of hepcidin (Hamp), the pivotal hormonal regulator of iron homeostasis, correlated with high levels of Fpn1 expression in hepatic Kupffer cells during postnatal development. Conversely, upon upregulation of Hamp expression at 12 weeks of age, Fpn1 expression decreased, indicative of a Hamp-mediated homeostatic loop. Aged cohorts of Pcm mice exhibited low levels of Fpn1 expression in the context of an iron-deficiency erythropoiesis and profound iron sequestration in reticuloendothelial macrophages, duodenum and other tissues. Similar to the anemia of chronic disease, these findings are consistent with decreased iron bioavailability due to sustained downregulation of Fpn1 levels by Hamp. Therefore, iron-deficiency erythropoiesis marks both the beginning and the endpoint of the hematopoietic defects in Pcm mice. However, whereas the embryonic/perinatal anemia results from primary organismal iron deficiency, adult Pcm mice develop anemia due to decreased iron bioavailability despite organismal iron overload. The polycythemia develops at the transition phase between the two disease states, governed by unimpeded Epo signaling. We conclude that regulatory alleles, such as Pcm, with highly dynamic changes in iron balance are ideally suited to interrogate the genetic circuitry regulating iron metabolism.

scholarly journals The Interplay between Drivers of Erythropoiesis and Iron Homeostasis in Rare Hereditary Anemias: Tipping the Balance

2021 ◽  
Vol 22 (4) ◽  
pp. 2204
Author(s):  
Simon Grootendorst ◽  
Jonathan de Wilde ◽  
Birgit van Dooijeweert ◽  
Annelies van Vuren ◽  
Wouter van Solinge ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Significant Problem ◽  
Blood Transfusions ◽  
Intrinsic Defects ◽  
Chronic Anemia ◽  
Erythroid Development ◽  
Disease Specific

Rare hereditary anemias (RHA) represent a group of disorders characterized by either impaired production of erythrocytes or decreased survival (i.e., hemolysis). In RHA, the regulation of iron metabolism and erythropoiesis is often disturbed, leading to iron overload or worsening of chronic anemia due to unavailability of iron for erythropoiesis. Whereas iron overload generally is a well-recognized complication in patients requiring regular blood transfusions, it is also a significant problem in a large proportion of patients with RHA that are not transfusion dependent. This indicates that RHA share disease-specific defects in erythroid development that are linked to intrinsic defects in iron metabolism. In this review, we discuss the key regulators involved in the interplay between iron and erythropoiesis and their importance in the spectrum of RHA.

Iron Homeostasis and Disorders in Dogs and Cats: A Review

2011 ◽  
Vol 47 (3) ◽  
pp. 151-160 ◽  
Author(s):  
Jennifer L. McCown ◽  
Andrew J. Specht
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Diagnostic Testing ◽  
Clinical Manifestations ◽  
Essential Element ◽  
The Body ◽  
Deficiency Anemia ◽  
Enzyme Systems ◽  
Living Organisms

Iron is an essential element for nearly all living organisms and disruption of iron homeostasis can lead to a number of clinical manifestations. Iron is used in the formation of both hemoglobin and myoglobin, as well as numerous enzyme systems of the body. Disorders of iron in the body include iron deficiency anemia, anemia of inflammatory disease, and iron overload. This article reviews normal iron metabolism, disease syndromes of iron imbalance, diagnostic testing, and treatment of either iron deficiency or excess. Recent advances in diagnosing iron deficiency using reticulocyte indices are reviewed.

Hepcidin in Iron Homeostasis: Diagnostic and Therapeutic Implications in Type 2 Diabetes Mellitus Patients

2017 ◽  
Vol 138 (4) ◽  
pp. 183-193 ◽  
Author(s):  
Sintayehu Ambachew ◽  
Belete Biadgo
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Diabetic Patients ◽  
Hepatitis C Infection ◽  
Body Iron

The prevalence of type 2 diabetes is increasing in epidemic proportions worldwide. Evidence suggests body iron overload is frequently linked and observed in patients with type 2 diabetes. Body iron metabolism is based on iron conservation and recycling by which only a part of the daily need is replaced by duodenal absorption. The principal liver-produced peptide called hepcidin plays a fundamental role in iron metabolism. It directly binds to ferroportin, the sole iron exporter, resulting in the internalization and degradation of ferroportin. However, inappropriate production of hepcidin has been shown to play a role in the pathogenesis of type 2 diabetes mellitus and its complications, based on the regulation and expression in iron-abundant cells. Underexpression of hepcidin results in body iron overload, which triggers the production of reactive oxygen species simultaneously thought to play a major role in diabetes pathogenesis mediated both by β-cell failure and insulin resistance. Increased hepcidin expression results in increased intracellular sequestration of iron, and is associated with the complications of type 2 diabetes. Besides, hepcidin concentrations have been linked to inflammatory cytokines, matriptase 2, and chronic hepatitis C infection, which have in turn been reported to be associated with diabetes by several approaches. Either hepcidin-targeted therapy alone or as adjunctive therapy with phlebotomy, iron chelators, or dietary iron restriction may be able to alter iron parameters in diabetic patients. Therefore, measuring hepcidin may improve differential diagnosis and the monitoring of disorders of iron metabolism.

scholarly journals σIfromBacillus subtilis: Impact on Gene Expression and Characterization of σI-Dependent Transcription That Requires New Types of Promoters with Extended −35 and −10 Elements

2018 ◽  
Vol 200 (17) ◽  
Author(s):  
Olga Ramaniuk ◽  
Martin Převorovský ◽  
Jiří Pospíšil ◽  
Dragana Vítovská ◽  
Olga Kofroňová ◽  
...  
Keyword(s):  
Gene Expression ◽  
Bacillus Subtilis ◽  
Iron Metabolism ◽  
Transcription Initiation ◽  
Iron Homeostasis ◽  
Model Organism ◽  
Content Type ◽  
Σ Factor

ABSTRACTThe σIsigma factor fromBacillus subtilisis a σ factor associated with RNA polymerase (RNAP) that was previously implicated in adaptation of the cell to elevated temperature. Here, we provide a comprehensive characterization of this transcriptional regulator. By transcriptome sequencing (RNA-seq) of wild-type (wt) and σI-null strains at 37°C and 52°C, we identified ∼130 genes affected by the absence of σI. Further analysis revealed that the majority of these genes were affected indirectly by σI. The σIregulon, i.e., the genes directly regulated by σI, consists of 16 genes, of which eight (thedhbandykuoperons) are involved in iron metabolism. The involvement of σIin iron metabolism was confirmed phenotypically. Next, we set up anin vitrotranscription system and defined and experimentally validated the promoter sequence logo that, in addition to −35 and −10 regions, also contains extended −35 and −10 motifs. Thus, σI-dependent promoters are relatively information rich in comparison with most other promoters. In summary, this study supplies information about the least-explored σ factor from the industrially important model organismB. subtilis.IMPORTANCEIn bacteria, σ factors are essential for transcription initiation. Knowledge about their regulons (i.e., genes transcribed from promoters dependent on these σ factors) is the key for understanding how bacteria cope with the changing environment and could be instrumental for biotechnologically motivated rewiring of gene expression. Here, we characterize the σIregulon from the industrially important model Gram-positive bacteriumBacillus subtilis. We reveal that σIaffects expression of ∼130 genes, of which 16 are directly regulated by σI, including genes encoding proteins involved in iron homeostasis. Detailed analysis of promoter elements then identifies unique sequences important for σI-dependent transcription. This study thus provides a comprehensive view on this underexplored component of theB. subtilistranscription machinery.

Multiple Causes of Iron Overload In Tissues, Cells and Subcellular Compartments

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. SCI-27-SCI-27
Author(s):  
Tracey Rouault
Keyword(s):  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Uptake ◽  
Iron Homeostasis ◽  
Regulatory Protein ◽  
Cluster Assembly ◽  
Iron Sulfur Cluster ◽  
Sulfur Cluster ◽  
Iron Sulfur ◽  
Mitochondrial Iron

Abstract Abstract SCI-27 Iron metabolism is regulated in mammals to assure that adequate iron is delivered to the hematopoietic system to support erythropoiesis. In systemic iron metabolism, regulation of both iron uptake from the diet and release from erythrophagocytosing macrophages is coordinated by action of the peptide hormone, hepcidin, which inhibits activity of the iron exporter, ferroportin. In general, high expression of hepcidin diminishes duodenal iron uptake and reduces macrophage iron release, a combination observed in the anemia of chronic disease. Low expression of hepcidin, which is synthesized by hepatocytes and influenced by transferrin receptor 2, HFE, hemojuvelin and bone morphogenetic receptors, facilitates iron uptake. Mutations affecting genes in the hepcidin pathway cause hemochromatosis, characterized by systemic iron overload that affects mainly hepatocytes and cardiac myocytes, but spares the CNS. In contrast, there are several degenerative diseases of the CNS in which neuronal iron overload is prominent and may play a causal role. The underlying pathophysiologies of neuronal brain iron accumulation syndromes remain unclear, even though several causal genes have been identified, including pantothenate kinase 2 and aceruloplasminemia. In some cases, increased iron may be inaccessible, and cells may suffer from functional iron insufficiency, as we propose for animals that lack iron regulatory protein 2. It is also possible that errors in subcellular iron metabolism can lead to mitochondrial iron overload and concomitant cytosolic iron deficiency, a combination observed in Friedreich ataxia, ISCU myopathy, and the sideroblastic anemia caused by glutaredoxin 5 deficiency. In each of these diseases, mitochondrial iron-sulfur cluster assembly is impaired, and it appears that normal regulation of mitochondrial iron homeostasis depends on intact iron-sulfur cluster assembly. Finally, in heme oxygenase 1 deficient animals, macrophages in the spleen and liver die upon erythrophagocytosis, and failure to normally metabolize heme leads to shift of heme iron to proximal tubules and macrophages of the kidney. Thus, treatment of “iron overload” must depend on the underlying causes, and removal of iron is appropriate in hemochromatosis, but more specific forms of therapy are needed for other forms of iron overload. 1. Ye, H. & Rouault, T. A. (2010). Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease. Biochemistry 49, 4945–4956. 2. Zhang, A. S. & Enns, C. A. (2009). Molecular mechanisms of normal iron homeostasis. Hematology Am Soc Hematol Educ Program 207–214. 3. Ye, H., Jeong, S. Y., Ghosh, M. C., Kovtunovych, G., Silvestri, L., Ortillo, D., Uchida, N., Tisdale, J., Camaschella, C. & Rouault, T. A. (2010). Glutaredoxin 5 deficiency causes sideroblastic anemia by specifically impairing heme biosynthesis and depleting cytosolic iron in human erythroblasts. J Clin Invest 120, 1749–1761. 4. Ghosh, M. C., Tong, W. H., Zhang, D., Ollivierre-Wilson, H., Singh, A., Krishna, M. C., Mitchell, J. B. & Rouault, T. A. (2008). Tempol-mediated activation of latent iron regulatory protein activity prevents symptoms of neurodegenerative disease in IRP2 knockout mice. Proc Natl Acad Sci U S A 105, 12028–12033. 5. Crooks, D. R., Ghosh, M. C., Haller, R. G., Tong, W. H. & Rouault, T. A. (2010). Posttranslational stability of the heme biosynthetic enzyme ferrochelatase is dependent on iron availability and intact iron-sulfur cluster assembly machinery. Blood 115, 860–869. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Iron-deficiency anemia from matriptase-2 inactivation is dependent on the presence of functional Bmp6

Blood ◽  
2011 ◽  
Vol 117 (2) ◽  
pp. 647-650 ◽  
Author(s):  
Anne Lenoir ◽  
Jean-Christophe Deschemin ◽  
Léon Kautz ◽  
Andrew J. Ramsay ◽  
Marie-Paule Roth ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Serine Protease ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Hepatic Iron ◽  
Master Regulator ◽  
Liver Iron ◽  
The Relationship

Abstract Hepcidin is the master regulator of iron homeostasis. In the liver, iron-dependent hepcidin activation is regulated through Bmp6 and its membrane receptor hemojuvelin (Hjv), whereas, in response to iron deficiency, hepcidin repression seems to be controlled by a pathway involving the serine protease matriptase-2 (encoded by Tmprss6). To determine the relationship between Bmp6 and matriptase-2 pathways, Tmprss6−/− mice (characterized by increased hepcidin levels and anemia) and Bmp6−/− mice (exhibiting severe iron overload because of hepcidin deficiency) were intercrossed. We showed that loss of Bmp6 decreased hepcidin levels; increased hepatic iron; and, importantly, corrected hematologic abnormalities in Tmprss6−/− mice. This finding suggests that elevated hepcidin levels in patients with familial iron-refractory, iron-deficiency anemia are the result of excess signaling through the Bmp6/Hjv pathway.

scholarly journals Iron Reduces M1 Macrophage Polarization in RAW264.7 Macrophages Associated with Inhibition of STAT1

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Zhen-Shun Gan ◽  
Qian-Qian Wang ◽  
Jia-Hui Li ◽  
Xu-Liang Wang ◽  
Yi-Zhen Wang ◽  
...  
Keyword(s):  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Macrophage Polarization ◽  
Reticuloendothelial System ◽  
Molecular Signature ◽  
Mrna Levels ◽  
M1 Macrophages ◽  
Iron Storage ◽  
Raw264.7 Macrophages ◽  
M1 Macrophage

Iron metabolism in inflammation has been mostly characterized in macrophages exposed to pathogens or inflammatory conditions. The aim of this study is to investigate the cross-regulatory interactions between M1 macrophage polarization and iron metabolism. Firstly, we characterized the transcription of genes related to iron homeostasis in M1 RAW264.7 macrophages stimulated by IFN-γ. The molecular signature of M1 macrophages showed high levels of iron storage (ferritin), a low level of iron export (ferroportin), and changes of iron regulators (hepcidin and transferrin receptors), which favour iron sequestration in the reticuloendothelial system and are benefit for inflammatory disorders. Then, we evaluated the effect of iron on M1 macrophage polarization. Iron significantly reduced mRNA levels of IL-6, IL-1β, TNF-α, and iNOS produced by IFN-γ-polarized M1 macrophages. Immunofluorescence analysis showed that iron also reduced iNOS production. However, iron did not compromise but enhanced the ability of M1-polarized macrophages to phagocytose FITC-dextran. Moreover, we demonstrated that STAT1 inhibition was required for reduction of iNOS and M1-related cytokines production by the present of iron. Together, these findings indicated that iron decreased polarization of M1 macrophages and inhibited the production of the proinflammatory cytokines. The results expanded our knowledge about the role of iron in macrophage polarization.

scholarly journals Defective Slc7a7 transport reduces systemic arginine availability compromising erythropoiesis and iron homeostasis

2021 ◽  
Author(s):  
Fernando Sotillo ◽  
Judith Giroud-Gerbetant ◽  
Jorge Couso ◽  
Rafael Artuch ◽  
Antonio Zorzano ◽  
...  
Keyword(s):  
Amino Acid ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Basolateral Membrane ◽  
M Cell ◽  
Cationic Amino Acid ◽  
Ferroportin 1 ◽  
Lysinuric Protein ◽  
Wide Variability

Slc7a7 encodes for y+LAT1, a transporter of cationic amino acid across the basolateral membrane of epithelial cells. Mutations in SLC7A7 gene give rise to Lysinuric Protein Intolerance (LPI), a rare autosomal recessive disease with wide variability of complications. Intriguingly, y+LAT1 is also involved in arginine transport in non polarized cells such as macrophages. Here we report that complete inducible Slc7a7 ablation in mouse compromises systemic arginine availability that alters proper erythropoiesis and that dysfunctional RBC generation leads to increased erythrophagocytosis, iron overload and an altered iron metabolism by macrophages. Herein, uncovering a novel mechanism that links amino acid metabolism to erythropoiesis and iron metabolism. Mechanistically, the iron exporter ferroportin-1 expression was compromised by increased plasma hepcidin causing macrophage iron accumulation. Strikingly, lysozyme M-cell-specific knockout mice failed to reproduce the total knockout alterations, while bone marrow transplantation experiments resulted in the resolution of macrophage iron overload but could not overcome erythropoietic defect. This study establishes a new crucial link between systemic arginine availability in erythropoiesis and iron homeostasis.

scholarly journals A Study of Serum Iron Profile in Patients with Chronic Kidney Disease

2020 ◽  
Vol 7 (6) ◽  
pp. A253-257
Author(s):  
Indira Shastry ◽  
Sushma Belurkar
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Iron Overload ◽  
Acute Phase ◽  
Serum Iron ◽  
Acute Phase Reaction ◽  
Phase Reaction ◽  
Anemia Of Chronic Disease ◽  
Iron Profile

Background: Even though anemia and iron deficiency can increase the morbidity and mortality in patients with chronic kidney disease (CKD), an iron overload can be dangerous as well. Aim: Identify the number of CKD patients with iron deficiency, iron overload, acute phase reaction and anemia of chronic disease in a tertiary care hospital. Material and methods: The study was conducted in Kasturba medical college, Manipal. 154 patients with CKD were selected for the study irrespective of their treatment status with hematinics and/or erythropoietin. Results: The mean total serum iron levels were 61μg/dl, Total Iron Binding Capacity (TIBC) 216.43 μg/dl, serum ferritin 539.68 μg/dl, and transferrin saturation of 32.18% respectively. When the serum iron profile of individuals was analyzed, majority (54.25%) of the patients were found to have acute phase reaction and most of them were in advanced stage of renal failure. Normal serum iron profile was found in 37.2% patients, iron overload in 2.2%, anemia of chronic disease in 5.3% and iron deficiency in 1% cases. These findings were statistically significant with the P value of 0.001. Conclusion: Most common type of serum iron profile found in the study population was acute phase reaction (54%) and majority of them were in stage 5 renal failure. Hence, before beginning an iron therapy, all the patients with anemia in chronic kidney disease should be evaluated for body iron status to prevent iron overload.

scholarly journals An essential cell-autonomous role for hepcidin in cardiac iron homeostasis

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Samira Lakhal-Littleton ◽  
Magda Wolna ◽  
Yu Jin Chung ◽  
Helen C Christian ◽  
Lisa C Heather ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Metabolic Dysfunction ◽  
Cardiac Iron ◽  
Cardiac Iron Overload ◽  
A Cell ◽  
The Brain ◽  
Specific Deletion

Hepcidin is the master regulator of systemic iron homeostasis. Derived primarily from the liver, it inhibits the iron exporter ferroportin in the gut and spleen, the sites of iron absorption and recycling respectively. Recently, we demonstrated that ferroportin is also found in cardiomyocytes, and that its cardiac-specific deletion leads to fatal cardiac iron overload. Hepcidin is also expressed in cardiomyocytes, where its function remains unknown. To define the function of cardiomyocyte hepcidin, we generated mice with cardiomyocyte-specific deletion of hepcidin, or knock-in of hepcidin-resistant ferroportin. We find that while both models maintain normal systemic iron homeostasis, they nonetheless develop fatal contractile and metabolic dysfunction as a consequence of cardiomyocyte iron deficiency. These findings are the first demonstration of a cell-autonomous role for hepcidin in iron homeostasis. They raise the possibility that such function may also be important in other tissues that express both hepcidin and ferroportin, such as the kidney and the brain.

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