Systemic Iron Homeostasis

2013 ◽  
Vol 93 (4) ◽  
pp. 1721-1741 ◽  
Author(s):  
Tomas Ganz
Keyword(s):  
Host Defense ◽  
Recent Progress ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Iron Concentration ◽  
Cellular Iron ◽  
Inflammatory Signals ◽  
Iron Losses ◽  
Total Body

The iron hormone hepcidin and its receptor and cellular iron exporter ferroportin control the major fluxes of iron into blood plasma: intestinal iron absorption, the delivery of recycled iron from macrophages, and the release of stored iron from hepatocytes. Because iron losses are comparatively very small, iron absorption and its regulation by hepcidin and ferroportin determine total body iron content. Hepcidin is in turn feedback-regulated by plasma iron concentration and iron stores, and negatively regulated by the activity of erythrocyte precursors, the dominant consumers of iron. Hepcidin and ferroportin also play a role in host defense and inflammation, and hepcidin synthesis is induced by inflammatory signals including interleukin-6 and activin B. This review summarizes and discusses recent progress in molecular characterization of systemic iron homeostasis and its disorders, and identifies areas for further investigation.

The Regulation of Hepcidin and Its Effects on Systemic and Cellular Iron Metabolism

Hematology ◽  
2008 ◽  
Vol 2008 (1) ◽  
pp. 151-158 ◽  
Author(s):  
Mark D. Fleming
Keyword(s):  
Iron Metabolism ◽  
Blood Cells ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Peptide Hormone ◽  
Intestinal Cells ◽  
Cellular Physiology ◽  
Cellular Iron ◽  
Regulated Expression ◽  
Total Body

Abstract Systemic iron homeostasis depends on the regulated expression of hepcidin, a peptide hormone that negatively regulates iron egress from intestinal cells and macrophages by altering the expression of the cellular iron exporter ferroportin. In doing so, hepcidin can control both the total body iron by modulating intestinal iron absorption as well as promote iron available for erythropoiesis by affecting the efficiency with which macrophages recycle iron from effete red blood cells. This review focuses on the systemic and cellular physiology of hepcidin regulation in relation to iron stores, erythropoiesis, inflammation, and hypoxia and how hepcidin regulation and dysregulation contributes to normal iron homeostasis and iron metabolism disorders.

scholarly journals Spontaneous iron overload in alpha-thalassemic mice

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 263-266
Author(s):  
DB Van Wyck ◽  
RA Popp ◽  
J Foxley ◽  
MH Witte ◽  
CL Witte ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Iron Concentration ◽  
Human Condition ◽  
Sham Operation ◽  
Liver And Kidney ◽  
Total Body ◽  
Chain Synthesis

Because clinical disorders of spontaneous iron overload have no experimental counterpart, we studied iron distribution (atomic absorption analysis) and intestinal absorption (59Fe) in mice with hereditary alpha-thalassemia. Mice heterozygous for a radiation-induced alpha-Hb gene deletion exhibit a mild hemolytic anemia, like the human condition, with microcytosis, reticulocytosis, splenomegaly, and chemical evidence of defective alpha-chain synthesis. Quantitative iron determination showed that total iron content in spleen, liver, and kidney, but not heart or lung, of adult alpha-thalassemic mice was greater (P less than .05) than that in unaffected littermates. Iron concentration was also increased in liver (P less than .001), spleen (P = .025), kidney (P = .058), and heart (P = .010); in general, the greater the iron concentration in liver, the greater that in spleen (r = .39, P = .009), kidney (r = .70, P less than .001), and heart (r = .46, P less than .001). In mice examined 8 months postoperatively, splenectomy, as compared to sham operation, significantly raised iron content in extrasplenic tissues, but did not affect total body iron. At 10–11 weeks of age, but no longer at 12–14 weeks, thalassemic mice showed higher rates of iron absorption than age-matched controls. Thus, alpha-thalassemic mice display an early occurring iron absorption defect, leading to a modest, sustained, nonprogressive iron overload, and thereby represent a valuable model for exploring disorders of iron homeostasis.

scholarly journals Spontaneous iron overload in alpha-thalassemic mice

Blood ◽  
1984 ◽  
Vol 64 (1) ◽  
pp. 263-266 ◽  
Author(s):  
DB Van Wyck ◽  
RA Popp ◽  
J Foxley ◽  
MH Witte ◽  
CL Witte ◽  
...  
Keyword(s):  
Iron Overload ◽  
Iron Content ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Iron Concentration ◽  
Human Condition ◽  
Sham Operation ◽  
Liver And Kidney ◽  
Total Body ◽  
Chain Synthesis

Abstract Because clinical disorders of spontaneous iron overload have no experimental counterpart, we studied iron distribution (atomic absorption analysis) and intestinal absorption (59Fe) in mice with hereditary alpha-thalassemia. Mice heterozygous for a radiation-induced alpha-Hb gene deletion exhibit a mild hemolytic anemia, like the human condition, with microcytosis, reticulocytosis, splenomegaly, and chemical evidence of defective alpha-chain synthesis. Quantitative iron determination showed that total iron content in spleen, liver, and kidney, but not heart or lung, of adult alpha-thalassemic mice was greater (P less than .05) than that in unaffected littermates. Iron concentration was also increased in liver (P less than .001), spleen (P = .025), kidney (P = .058), and heart (P = .010); in general, the greater the iron concentration in liver, the greater that in spleen (r = .39, P = .009), kidney (r = .70, P less than .001), and heart (r = .46, P less than .001). In mice examined 8 months postoperatively, splenectomy, as compared to sham operation, significantly raised iron content in extrasplenic tissues, but did not affect total body iron. At 10–11 weeks of age, but no longer at 12–14 weeks, thalassemic mice showed higher rates of iron absorption than age-matched controls. Thus, alpha-thalassemic mice display an early occurring iron absorption defect, leading to a modest, sustained, nonprogressive iron overload, and thereby represent a valuable model for exploring disorders of iron homeostasis.

scholarly journals Molecular mechanisms of normal iron homeostasis

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 207-214 ◽  
Author(s):  
An-Sheng Zhang ◽  
Caroline A. Enns
Keyword(s):  
Iron Homeostasis ◽  
Molecular Mechanisms ◽  
Iron Absorption ◽  
Hypoxia Inducible Factor ◽  
Bmp Signaling ◽  
Control Mechanisms ◽  
Iron Regulatory Proteins ◽  
Hepcidin Expression ◽  
Cellular Iron ◽  
Morphogenetic Protein

Abstract Humans possess elegant control mechanisms to maintain iron homeostasis by coordinately regulating iron absorption, iron recycling, and mobilization of stored iron. Dietary iron absorption is regulated locally by hypoxia inducible factor (HIF) signaling and iron-regulatory proteins (IRPs) in enterocytes and systematically by hepatic hepcidin, the central iron regulatory hormone. Hepcidin not only controls the rate of iron absorption but also determines iron mobilization from stores through negatively modulating the function of ferroportin, the only identified cellular iron exporter to date. The regulation of hepatic hepcidin is accomplished by the coordinated activity of multiple proteins through different signaling pathways. Recent studies have greatly expanded the knowledge in the understanding of hepcidin expression and regulation by the bone morphogenetic protein (BMP) signaling, the erythroid factors, and inflammation. In this review, we mainly focus on the roles of recently identified proteins in the regulation of iron homeostasis.

scholarly journals A recall-by-genotype study on polymorphisms in the TMPRSS6 gene and oral iron absorption: a study protocol

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 701 ◽  
Author(s):  
Momodou W. Jallow ◽  
Susana Campino ◽  
Andrew M. Prentice ◽  
Carla Cerami
Keyword(s):  
High Frequency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Association Studies ◽  
Iron Concentration ◽  
West African ◽  
Oral Iron ◽  
Negative Regulator ◽  
Genome Wide Association Studies ◽  
Increased Risk

Background: Oral iron supplementation is commonly used to treat and prevent anaemia. The transmembrane protease serine 6 gene (TMPRSS6), which encodes matriptase 2, is a negative regulator of hepcidin, the key controller of iron homeostasis. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia.  We will investigate the in vivo effects of three previously reported TMPRSS6 variants (rs855791, rs4820268 and rs2235321) on oral iron absorption in non-anaemic volunteers in The Gambia. Methods: A recall-by-genotype study design will be employed. Pre-genotyped participants will be recruited from the West African BioResouce (WABR), which currently contains over 3000 genotyped individuals. Male and female volunteers will be selected based on polymorphisms (rs855791, rs4820268 and rs2235321) in the TMPRSS6 gene in the Gambian population. The effects of a single variant allele at one SNP and the additive effect of two or three variant alleles from either two or all three SNPs will be investigated. Study participants will be given a single oral dose of 400mg ferrous sulfate, and blood samples will be collected at baseline, two hours and five hours post supplementation. Differences in iron absorption between genotype groups will be assessed by measuring the increase in serum iron concentration at five hours post iron ingestion. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption. This may help in guiding future iron intervention strategies, particularly in populations with a high frequency of these SNPs and a high frequency of anaemia. Study registration: ClinicalTrials.gov NCT03341338 14/11/17.

Iron and hepcidin: a story of recycling and balance

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 1-8 ◽  
Author(s):  
Clara Camaschella
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Homeostasis ◽  
Inflammatory Diseases ◽  
Beta Thalassemia ◽  
Genetic Inactivation ◽  
Cellular Iron ◽  
Iron Sequestration ◽  
Total Body

Abstract To avoid iron deficiency and overload, iron availability is tightly regulated at both the cellular and systemic levels. The liver peptide hepcidin controls iron flux to plasma from enterocytes and macrophages through degradation of the cellular iron exporter ferroportin. The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle. Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia. Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.

scholarly journals Hepcidin-Ferroportin Interaction Controls Systemic Iron Homeostasis

2021 ◽  
Vol 22 (12) ◽  
pp. 6493
Author(s):  
Elizabeta Nemeth ◽  
Tomas Ganz
Keyword(s):  
Iron Deficiency ◽  
Iron Homeostasis ◽  
Genetic Diseases ◽  
Hereditary Hemochromatosis ◽  
Iron Concentration ◽  
Extracellular Fluid ◽  
Peptide Hormone ◽  
Cellular Iron ◽  
The Stability ◽  
Iron Delivery

Despite its abundance in the environment, iron is poorly bioavailable and subject to strict conservation and internal recycling by most organisms. In vertebrates, the stability of iron concentration in plasma and extracellular fluid, and the total body iron content are maintained by the interaction of the iron-regulatory peptide hormone hepcidin with its receptor and cellular iron exporter ferroportin (SLC40a1). Ferroportin exports iron from duodenal enterocytes that absorb dietary iron, from iron-recycling macrophages in the spleen and the liver, and from iron-storing hepatocytes. Hepcidin blocks iron export through ferroportin, causing hypoferremia. During iron deficiency or after hemorrhage, hepcidin decreases to allow iron delivery to plasma through ferroportin, thus promoting compensatory erythropoiesis. As a host defense mediator, hepcidin increases in response to infection and inflammation, blocking iron delivery through ferroportin to blood plasma, thus limiting iron availability to invading microbes. Genetic diseases that decrease hepcidin synthesis or disrupt hepcidin binding to ferroportin cause the iron overload disorder hereditary hemochromatosis. The opposite phenotype, iron restriction or iron deficiency, can result from genetic or inflammatory overproduction of hepcidin.

scholarly journals Hepcidin in iron overload disorders

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 4103-4105 ◽  
Author(s):  
George Papanikolaou ◽  
Michalis Tzilianos ◽  
John I. Christakis ◽  
Dionisios Bogdanos ◽  
Konstantina Tsimirika ◽  
...  
Keyword(s):  
Iron Overload ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Hereditary Hemochromatosis ◽  
Congenital Dyserythropoietic Anemia ◽  
Cellular Iron ◽  
Juvenile Hemochromatosis ◽  
Hepcidin Gene

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.

scholarly journals A recall-by-genotype study on polymorphisms in the TMPRSS6 gene and oral iron absorption: a study protocol

F1000Research ◽  
2021 ◽  
Vol 8 ◽  
pp. 701
Author(s):  
Momodou W. Jallow ◽  
Susana Campino ◽  
Andrew M. Prentice ◽  
Carla Cerami
Keyword(s):  
High Frequency ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Association Studies ◽  
Iron Concentration ◽  
West African ◽  
Oral Iron ◽  
Negative Regulator ◽  
Genome Wide Association Studies ◽  
Increased Risk

Background: Oral iron supplementation is commonly used to treat and prevent anaemia. The transmembrane protease serine 6 gene (TMPRSS6), which encodes matriptase 2, is a negative regulator of hepcidin, the key controller of iron homeostasis. Genome-wide association studies (GWAS) have identified several single nucleotide polymorphisms (SNPs) in the TMPRSS6 gene that are associated with an increased risk of iron-deficiency anaemia.  We will investigate the in vivo effects of three previously reported TMPRSS6 variants (rs855791, rs4820268 and rs2235321) on oral iron absorption in non-anaemic volunteers in The Gambia. Methods: A recall-by-genotype study design will be employed. Pre-genotyped participants will be recruited from the West African BioResouce (WABR), which currently contains over 3000 genotyped individuals. Male and female volunteers will be selected based on polymorphisms (rs855791, rs4820268 and rs2235321) in the TMPRSS6 gene in the Gambian population. The effects of a single variant allele at one SNP and the additive effect of two or three variant alleles from either two or all three SNPs will be investigated. Study participants will be given a single oral dose of 400mg ferrous sulfate, and blood samples will be collected at baseline, two hours and five hours post supplementation. Differences in iron absorption between genotype groups will be assessed by measuring the increase in serum iron concentration at five hours post iron ingestion. Discussion: This study will increase understanding of the role of genetic variations in TMPRSS6 on oral iron absorption in subjects of West African origin. This will test for the biological basis for the association of each of the three TMPRSS6 variants with iron absorption. This may help in guiding future iron intervention strategies, particularly in populations with a high frequency of these SNPs and a high frequency of anaemia. Study registration: ClinicalTrials.gov NCT03341338 14/11/17.

scholarly journals RNF217 regulates iron homeostasis through its E3 ubiquitin ligase activity by modulating ferroportin degradation

Blood ◽  
2021 ◽  
Author(s):  
Li Jiang ◽  
Jiaming Wang ◽  
Kai Wang ◽  
Hao Wang ◽  
Qian Wu ◽  
...  
Keyword(s):  
Ubiquitin Ligase ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
E3 Ubiquitin Ligase ◽  
Conditional Knockout ◽  
Conditional Knockout Mouse ◽  
Ubiquitin Ligase Activity ◽  
Subsequent Degradation ◽  
Identification And Characterization

Ferroportin (FPN), the body's sole iron exporter, is essential for maintaining systemic iron homeostasis. In response to either increased iron or inflammation, hepatocyte-secreted hepcidin binds to FPN, inducing its internalization and subsequent degradation. However, the E3 ubiquitin ligase that underlies FPN degradation has not been identified. Here, we report the identification and characterization of a novel mechanism involving the RNF217-mediated degradation of FPN. A combination of two different E3 screens revealed that the Rnf217 gene is a target of Tet1, mediating the ubiquitination and subsequent degradation of FPN. Interestingly, loss of Tet1 expression causes an accumulation of FPN and an impaired response to iron overload, manifested by increased iron accumulation in the liver together with decreased iron in the spleen and duodenum. Moreover, we found that the degradation and ubiquitination of FPN could be attenuated by mutating RNF217. Finally, using two conditional knockout mouse lines, we found that knocking out Rnf217 in macrophages increases splenic iron export by stabilizing FPN, whereas knocking out Rnf217 in intestinal cells appears to increase iron absorption. These findings suggest that the Tet1-RNF217-FPN axis regulates iron homeostasis, revealing new therapeutic targets for FPN-related diseases.

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