scholarly journals Modulation of intestinal sulfur assimilation metabolism regulates iron homeostasis

2018 ◽  
Vol 115 (12) ◽  
pp. 3000-3005 ◽  
Author(s):  
Benjamin H. Hudson ◽  
Andrew T. Hale ◽  
Ryan P. Irving ◽  
Shenglan Li ◽  
John D. York
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Reduction ◽  
Genetic Basis ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Sulfur Assimilation ◽  
Nucleotide Hydrolysis ◽  
Evolutionarily Conserved ◽  
Organismal Development

Sulfur assimilation is an evolutionarily conserved pathway that plays an essential role in cellular and metabolic processes, including sulfation, amino acid biosynthesis, and organismal development. We report that loss of a key enzymatic component of the pathway, bisphosphate 3′-nucleotidase (Bpnt1), in mice, both whole animal and intestine-specific, leads to iron-deficiency anemia. Analysis of mutant enterocytes demonstrates that modulation of their substrate 3′-phosphoadenosine 5′-phosphate (PAP) influences levels of key iron homeostasis factors involved in dietary iron reduction, import and transport, that in part mimic those reported for the loss of hypoxic-induced transcription factor, HIF-2α. Our studies define a genetic basis for iron-deficiency anemia, a molecular approach for rescuing loss of nucleotidase function, and an unanticipated link between nucleotide hydrolysis in the sulfur assimilation pathway and iron homeostasis.

scholarly journals Molecular Aspects and Treatment of Iron Deficiency in the Elderly

2020 ◽  
Vol 21 (11) ◽  
pp. 3821
Author(s):  
Antonino Davide Romano ◽  
Annalisa Paglia ◽  
Francesco Bellanti ◽  
Rosanna Villani ◽  
Moris Sangineto ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Diagnostic Algorithm ◽  
The Elderly ◽  
Deficiency Anemia ◽  
Clinical State ◽  
Ageing Population ◽  
Gastrointestinal Lesions ◽  
Aged Subjects

Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease.

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.

An Essential Role For Transferrin Receptor 2 In Erythropoiesis During Iron Restriction

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 429-429
Author(s):  
Daniel F Wallace ◽  
Cameron J McDonald ◽  
Eriza S Secondes ◽  
Lesa Ostini ◽  
Gautam Rishi ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Deficiency Anemia ◽  
Transferrin Receptor ◽  
Iron Homeostasis ◽  
Hereditary Hemochromatosis ◽  
Deficiency Anemia ◽  
Erythroid Cells ◽  
Iron Restriction ◽  
Extramedullary Erythropoiesis

Abstract Iron deficiency and iron overload are common clinical conditions that impact on the health and wellbeing of up to 30% of the world’s population. Understanding mechanisms regulating iron homeostasis will provide improved strategies for treating these disorders. The liver-expressed proteins matriptase-2 (encoded by TMPRSS6), HFE and transferrin receptor 2 (TFR2) play important and opposing roles in systemic iron homeostasis by regulating expression of the iron regulatory hormone hepcidin. Mutations in TMPRSS6 lead to iron refractory iron deficiency anemia, whereas mutations in HFE and TFR2 lead to the iron overload disorder hereditary hemochromatosis. To elucidate the competing roles of these hepcidin regulators, we created mice lacking matriptase-2, Hfe and Tfr2. Tmprss6 -/-/Hfe-/-/Tfr2-/- mice had iron deficiency anemia resulting from hepatic hepcidin over-expression and activation of Smad1/5/8, indicating that matriptase-2 predominates over Hfe and Tfr2 in hepcidin regulation. Surprisingly, this anemia was more severe than in the Tmprss6-/- mice, demonstrated by more extensive alopecia, lower hematocrit and significant extramedullary erythropoiesis in the spleen. There was increased expression of erythroid-specific genes in the spleens of Tmprss6-/-/Hfe-/-/Tfr2-/- mice, consistent with the extramedullary erythropoiesis. Expression of Tfr2 but not Hfe in the spleen was increased in the Tmprss6-/- mice compared to wild type and correlated with the expression of erythroid genes, suggesting that Tfr2 is expressed in erythroid cells. Further analysis of gene expression in the bone marrow suggests that the loss of Tfr2 in the erythroid cells of Tmprss6-/-/Hfe-/-/Tfr2-/- mice causes a delay in the differentiation process leading to a more severe phenotype. In conclusion, our results indicate that Hfe and Tfr2 act upstream of matriptase-2 in hepcidin regulation or in a way that is overridden when matriptase-2 is deleted. These results indicate that inhibition of matriptase-2 would be useful in the treatment of iron overload conditions such as hereditary hemochromatosis. We have also identified a novel role for Tfr2 in erythroid differentiation that is separate from its canonical role as a regulator of iron homeostasis in the liver. This important role of Tfr2 in erythropoiesis only becomes apparent during conditions of iron restriction. Our results provide novel insights into mechanisms regulating and linking iron homeostasis and erythropoiesis. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A genome-wide meta-analysis yields 46 new loci associating with biomarkers of iron homeostasis

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Steven Bell ◽  
◽  
Andreas S. Rigas ◽  
Magnus K. Magnusson ◽  
Egil Ferkingstad ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Overload ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Meta Analysis ◽  
Deficiency Anemia ◽  
Genome Wide Association Studies ◽  
Independent Sequence ◽  
Genome Wide ◽  
A Genome

AbstractIron is essential for many biological functions and iron deficiency and overload have major health implications. We performed a meta-analysis of three genome-wide association studies from Iceland, the UK and Denmark of blood levels of ferritin (N = 246,139), total iron binding capacity (N = 135,430), iron (N = 163,511) and transferrin saturation (N = 131,471). We found 62 independent sequence variants associating with iron homeostasis parameters at 56 loci, including 46 novel loci. Variants at DUOX2, F5, SLC11A2 and TMPRSS6 associate with iron deficiency anemia, while variants at TF, HFE, TFR2 and TMPRSS6 associate with iron overload. A HBS1L-MYB intergenic region variant associates both with increased risk of iron overload and reduced risk of iron deficiency anemia. The DUOX2 missense variant is present in 14% of the population, associates with all iron homeostasis biomarkers, and increases the risk of iron deficiency anemia by 29%. The associations implicate proteins contributing to the main physiological processes involved in iron homeostasis: iron sensing and storage, inflammation, absorption of iron from the gut, iron recycling, erythropoiesis and bleeding/menstruation.

Revisiting Iron Metabolism, Iron Homeostasis and Iron Deficiency Anemia

2021 ◽  
Vol 67 (03/2021) ◽  
Author(s):  
Muhammad Saboor ◽  
Amtuz Zehra ◽  
Hassan Hamali ◽  
Abdullah Mobarki
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Metabolism ◽  
Iron Homeostasis ◽  
Deficiency Anemia

Comparison of Apical and Basolateral Cu Treatment for Iron-related Gene Regulation During Deferoxamine Induced Iron Deficiency Anemia

2021 ◽  
Author(s):  
Ezgi Evcan ◽  
sukru gulec
Keyword(s):  
Tissue Culture ◽  
Gene Regulation ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Deficiency Anemia ◽  
Copper Transporter ◽  
Culture Plate ◽  
Iron Deficient ◽  
Basolateral Side

Abstract Background: Intestinal copper transporter (Atp7a) mutant brindled mice with systemic Cu deficiency had elevated Cu levels in enterocyte cells without any perturbation of iron regulating genes, suggesting that blood Cu level might be important for intestinal iron homeostasis during iron deficiency anemia (IDA). We hypothesized that the blood Cu level and polarization (apical and basolateral) of enterocyte cells might be important regulators for the compensatory response on the regulation of genes in enterocyte cells during IDA. Methods: We grew Caco-2 cells on a bicameral cell culture plate to mimic the human intestine system and on a regular tissue culture plate. IDA was induced by Deferoxamine (DFO). The cells were treated with Cu and Cu with Fe following mRNA expressions of DMT1, FPN, TFR, and ANKRD37 were analyzed. Results: Our main finding was that basolateral treatment of Cu significantly reduced mRNA expressions of iron-regulated genes, including DMT1, FPN, TFR, and ANKRD37, compared to DFO treated and DFO with apical Cu treated groups in both bicameral and regular tissue culture plates. Conclusions: Cu level in the basolateral side of Caco-2 cells significantly influenced the intracellular gene regulation in DFO induced iron-deficient condition, and polarization of the cells might be important factor gene regulation in enterocyte cells.

scholarly journals Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis

Blood ◽  
2010 ◽  
Vol 115 (18) ◽  
pp. 3817-3826 ◽  
Author(s):  
Karin E. Finberg ◽  
Rebecca L. Whittlesey ◽  
Mark D. Fleming ◽  
Nancy C. Andrews
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Intravenous Iron ◽  
Deficiency Anemia ◽  
Mrna Levels ◽  
Loss Of Function ◽  
Down Regulation ◽  
Smad Signaling ◽  
Hepcidin Expression

Abstract Iron-refractory, iron-deficiency anemia (IRIDA) is a familial disorder characterized by iron deficiency anemia unresponsive to oral iron treatment but partially responsive to intravenous iron therapy. Previously, we showed that IRIDA patients harbor loss-of-function mutations in TMPRSS6, a type II transmembrane serine protease primarily expressed by the liver. Both humans and mice with TMPRSS6 mutations show inappropriately elevated levels of the iron-regulatory hormone hepcidin, suggesting that TMPRSS6 acts to negatively regulate hepcidin expression. Here we investigate the relationship between Tmprss6 and the bone morphogenetic protein (BMP)–Smad signaling pathway, a key pathway promoting hepcidin transcription in hepatocytes. We show that livers from mice deficient for Tmprss6 have decreased iron stores and decreased Bmp6 mRNA, but markedly increased mRNA for Id1, a target gene of Bmp6 signaling. In contrast, mice deficient for both Tmprss6 and hemojuvelin (Hjv), a BMP coreceptor that augments hepcidin expression in hepatocytes, showed markedly decreased hepatic levels of hepcidin and Id1 mRNA, markedly increased hepatic Bmp6 mRNA levels, and systemic iron overload similar to mice deficient for Hjv alone. These findings suggest that down-regulation of Bmp/Smad signaling by Tmprss6 is required for regulation of hepcidin expression and maintenance of systemic iron homeostasis.

scholarly journals Comparative Evaluation of Sucrosomial Iron and Iron Oxide Nanoparticles as Oral Supplements in Iron Deficiency Anemia in Piglets

2021 ◽  
Vol 22 (18) ◽  
pp. 9930
Author(s):  
Rafał Mazgaj ◽  
Paweł Lipiński ◽  
Mateusz Szudzik ◽  
Aneta Jończy ◽  
Zuzanna Kopeć ◽  
...  
Keyword(s):  
Iron Oxide ◽  
Iron Deficiency ◽  
Iron Oxide Nanoparticles ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Mammalian Species ◽  
Deficiency Anemia ◽  
Oxide Nanoparticles ◽  
Iron Supplement ◽  
Nutritional Disorder

Iron deficiency is the most common mammalian nutritional disorder. However, among mammalian species iron deficiency anemia (IDA), occurs regularly only in pigs. To cure IDA, piglets are routinely injected with high amounts of iron dextran (FeDex), which can lead to perturbations in iron homeostasis. Here, we evaluate the therapeutic efficacy of non-invasive supplementation with Sucrosomial iron (SI), a highly bioavailable iron supplement preventing IDA in humans and mice and various iron oxide nanoparticles (IONPs). Analysis of red blood cell indices and plasma iron parameters shows that not all iron preparations used in the study efficiently counteracted IDA comparable to FeDex-based supplementation. We found no signs of iron toxicity of any tested iron compounds, as evaluated based on the measurement of several toxicological markers that could indicate the occurrence of oxidative stress or inflammation. Neither SI nor IONPs increased hepcidin expression with alterations in ferroportin (FPN) protein level. Finally, the analysis of the piglet gut microbiota indicates the individual pattern of bacterial diversity across taxonomic levels, independent of the type of supplementation. In light of our results, SI but not IONPs used in the experiment emerges as a promising nutritional iron supplement, with a high potential to correct IDA in piglets.

Erythroid Growth Differentiation Factor 15 and Ferroportin Expression During Gestational Iron Deficiency Anemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 5286-5286
Author(s):  
Rekha Athiyarath ◽  
Kalaiselvi Sakthivel ◽  
Vinod J Abraham ◽  
Daisy Singh ◽  
Alok Srivastava ◽  
...  
Keyword(s):  
Gene Expression ◽  
Iron Deficiency ◽  
Pregnant Women ◽  
Iron Deficiency Anemia ◽  
Iron Homeostasis ◽  
Iron Absorption ◽  
Deficiency Anemia ◽  
Protein Levels ◽  
In Pregnancy

Abstract Abstract 5286 Iron homeostasis during pregnancy is modulated to meet the increased iron needs but how this is achieved is not very clear. Growth Differentiation Factor (GDF15) produced by the expanded erythroid compartment in β thalassemia has been shown to increase iron absorption by suppressing hepcidin. GDF15 is also highly expressed in the placenta and increasing levels of GDF15 are seen with advancing gestational age of pregnancy. But the role of GDF15 in iron homeostasis in pregnancy has not been elucidated till date. Ferroportin (FPN) is the only known protein involved in iron export and it is the target of hepcidin, the central regulator of iron homeostasis. In this study we analyzed the expression of GDF15 and FPN in pregnant women with iron deficiency anemia. Fourteen pregnant women with proven iron deficiency anemia (IDAP) [Hb<11g/dL and Ferritin <12ng/ul] and thirteen healthy subjects as controls (NC) were enrolled as part of an ongoing study. Serum GDF15 and hepcidin levels were measured by ELISA kits from R&D systems and Bachem, UK respectively. Reticulocytes were isolated and total RNA was purified using Trizol. GDF15 and FPN transcripts were quantified using Taqman Gene expression assays using GAPDH as an internal control. Gene expression values were calculated on the basis of the 2-ΔΔCt method. The mean age of the pregnant women was 22.5±2.5 years. The median ferritin in IDAP was 1.4 and ranged from 0.2 to 8.3 ng/ml. The hepcidin levels were very low [<2ng/ml] in IDAP. Serum GDF15 levels in IDAP was significantly higher as compared to controls [IDAP-3333.71±409 pg/ml vs. NC-309.7±127.0 pg/ml; p=0.000]. Reticulocyte GDF15 mRNA expression was significantly lower [IDAP-25.09 (1.28–239.8) vs. NC-910.4 (0.28–1962); p=0.004] and FPN expression was significantly higher in pregnancy [IDAP-209.8 (48.33–1201) vs. NC-77.96(17.21–281.3); p=0.001] than in the controls. GDF15 mRNA as well as serum GDF15 levels significantly correlated with FPN expression in IDAP [RNA r=0.895; p=0.000; Protein r=0.555, p=0.049] Eight patients were followed up after 8 weeks of supplementation and there was no significant change in the serum GDF15 concentration (3235±468.26pg/ml; p=1.000). However their serum ferritin and hepcidin levels were significantly higher [Ferritin-11.60 (9.80–21.30), p=0.0021; Hepcidin-17.86(0.29–38.50), p=0.015]. There was no significant correlation between GDF15 protein levels and hepcidin (r=0.429, p=0.354). Molecular mechanisms of iron homeostasis in pregnancy are poorly understood. IDAP had very low hepcidin levels which normalized after iron stores were replenished. Elevated GDF15 protein levels in IDAP inspite of low reticulocyte expression indicate that erythroid contribution is minimal and placenta is the main source of GDF15. The significant correlation between GDF15 (mRNA and protein) with FPN expression and absence of correlation with hepcidin levels indicate a possible role for GDF15 in iron homeostasis in pregnancy. These findings has to be validated and the role of GDF15 in modulating FPN and there by iron absorption has to be further elucidated. Disclosures: No relevant conflicts of interest to declare.

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