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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Iron is essential for many biological processes, including oxygen delivery, and its supply is tightly regulated. Hepcidin, a small peptide synthesized in the liver, is a key regulator of iron absorption and homeostasis in mammals. Hepcidin production is increased by iron overload and decreased by anemia and hypoxia; but the molecular mechanisms that govern the hepcidin response to these stimuli are not known. Here we establish that the von Hippel-Lindau/hypoxia-inducible transcription factor (VHL/HIF) pathway is an essential link between iron homeostasis and hepcidin regulation in vivo. Through coordinate downregulation of hepcidin and upregulation of erythropoietin and ferroportin, the VHL-HIF pathway mobilizes iron to support erythrocyte production.
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PMID:Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). 1755 18

Iron is a micronutrient that is an essential component that drives many metabolic reactions. Too little iron leads to anemia and too much iron increases the oxidative stress of body tissues leading to inflammation, cell death, and system organ dysfunction, including cancer. Maintaining normal iron balance is achieved by rigorous control of the amount absorbed by the intestine, that released from macrophages following erythrophagocytosis of effete red cells and by either release or uptake from hepatocytes. Hepcidin is a recently characterized molecule that appears to play a key role in the regulation of iron efflux from enterocytes, macrophages, and hepatocytes. It is produced by hepatocytes under basal conditions, in response to alterations in increased iron stores or reduced requirement for erythropoiesis and by inflammation. The proteins that regulate hepcidin expression are presently being defined, albeit that our present understanding is still far from complete. This review focuses on the molecules which regulate hepcidin expression. The subsequent characterization of these proteins using molecular, cellular, and physiological approaches also is discussed along with inflammatory signals and receptors involved in hepcidin expression.
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PMID:Molecular regulation of hepatic expression of iron regulatory hormone hepcidin. 1755 63

Hepcidin is an iron-regulatory protein that is upregulated in response to increased iron or inflammatory stimuli. Hepcidin reduces serum iron and induces iron sequestration in the reticuloendothelial macrophages - the hallmark of anaemia of inflammation. Iron deprivation is used as a defense mechanism against infection, and it also has a beneficial effect on the control of cancer. The tumour-suppressor p53 transcriptionally regulates genes involved in growth arrest, apoptosis and DNA repair, and perturbation of p53 pathways is a hallmark of the majority of human cancers. This study inspected a role of p53 in the transcriptional regulation of hepcidin. Based on preliminary bioinformatics analysis, we identified a putative p53 response-element (p53RE) contained in the hepcidin gene (HAMP) promoter. Chromatin immunoprecipitation (ChIP), reporter assays and a temperature sensitive p53 cell-line system were used to demonstrate p53 binding and activation of the hepcidin promoter. p53 bound to hepcidin p53RE in vivo, andthis p53RE could confer p53-dependent transcriptional activation. Activation of p53 increased hepcidin expression, while silencing of p53 resulted in decreased hepcidin expression in human hepatoma cells. Taken together, these results define HAMP as a novel transcriptional target of p53. We hypothesise that hepcidin upregulation by p53 is part of a defence mechanism against cancer, through iron deprivation. Hepcidin induction by p53 might be involved in the pathogenesis of anaemia accompanying cancer.
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PMID:Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53. 1759 32

Hepcidin is a peptide hormone secreted by the liver that plays a central role in the regulation of iron homeostasis. Increased hepcidin levels result in anemia while decreased expression is the causative feature in most primary iron overload diseases. Mutations in hemochromatosis type 2 (HFE2), which encodes the protein hemojuvelin (HJV), result in the absence of hepcidin and an early-onset form of iron overload disease. HJV is a bone morphogenetic protein (BMP) coreceptor and HJV mutants have impaired BMP signaling. In this issue of the JCI, Babitt and colleagues show that BMPs are autocrine hormones that induce hepcidin expression (see the related article beginning on page 1933). Administration of a recombinant, soluble form of HJV decreased hepcidin expression and increased serum iron levels by mobilizing iron from splenic stores. These results demonstrate that recombinant HJV may be a useful therapeutic agent for treatment of the anemia of chronic disease, a disorder resulting from high levels of hepcidin expression.
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PMID:Hepcidin regulation: ironing out the details. 1760 65

Hepcidin has been proposed as an important factor in the pathogenesis of the anaemia of chronic disease (ACD). The aim of this study was to assess the relationship between anaemia and inflammatory activity in patients with solid tumours. Patients were classified as having iron deficiency anaemia (IDA) (hypoferremia and hypoferretinemia), ACD (hypoferremia, normal or increased serum ferritin) and anaemia related to cancer (ARC) (no abnormalities in iron status). Serum pro-hepcidin, IL-6, C-reactive protein (CRP) and iron status parameters were measured using commercial kits. CRP and IL-6 levels were significantly higher in patients with ACD when compared to IDA, ARC and non anaemic patients (P < 0.005). Serum pro-hepcidin levels were not different among all studied groups (P = 0.138). A negative correlation was observed between haemoglobin and serum ferritin, CRP and IL-6 levels only in group of ACD. Serum pro-hepcidin concentrations were not correlated with degree of anaemia or iron metabolism parameters. According to our results the inflammatory activity represented by high levels of IL-6 and CRP are involved in the pathogenesis of ACD, probably due to the action of inflammation on iron metabolism, but not in ARC. It was not possible to demonstrate a significant effect of pro-hepcidin on the anaemia in cancer patients.
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PMID:Anaemia in patients with cancer: role of inflammatory activity on iron metabolism and severity of anaemia. 1787 9

Heme-regulated eIF2alpha kinase (HRI) plays an essential protective role in anemias of iron deficiency, erythroid protoporphyria, and beta-thalassemia. In this study, we report that HRI protein is present in murine macrophages, albeit at a lower level than in erythroid precursors. Hri-/- mice exhibited impaired macrophage maturation and a weaker antiinflammatory response with reduced cytokine production upon LPS challenge. The level of production of hepcidin, an important player in the pathogenesis of the anemia of inflammation, was significantly decreased in Hri-/- mice, accompanied by decreased splenic macrophage iron content and increased serum iron content. Hepcidin expression was also significantly lower, with a concomitant increase in serum iron in Hri-/- mice upon LPS treatment. We also demonstrated an impairment of erythrophagocytosis by Hri-/- macrophages both in vitro and in vivo under chronic hemolytic anemia, providing evidence for the role of HRI in recycling iron from senescent red blood cells. This work demonstrates that HRI deficiency attenuates hepcidin expression and iron homeostasis in mice, indicating a potential role for HRI in the anemia of inflammation.
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PMID:The function of heme-regulated eIF2alpha kinase in murine iron homeostasis and macrophage maturation. 1793 63

The pathogenesis of malarial anemia is incompletely understood. Hepcidin, a recently discovered peptide hormone, is a major regulator of iron metabolism and is thought to play a central role in the anemia of chronic inflammation. The specific aim of the study was to characterize the association between urinary hepcidin, hemoglobin, and parasitemia in 199 patients presenting for evaluation of Plasmodium falciparum malaria in Ghana. Urinary hepcidin was semi-quantitatively assessed using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. Urinary hepcidin (intensity/mmol creatinine) was associated with log parasitemia in 86 children (beta = 0.086, standard error [SE] = 0.035, P < 0.017), 31 pregnant women (beta = 0.218, SE = 0.085, P < 0.016), and 82 adults (beta = 0.184, SE =0.043, P < 0.0001). Urinary hepcidin was not significantly associated with hemoglobin or anemia. Urinary hepcidin is more strongly associated with parasitemia than hemoglobin or anemia among patients with acute P. falciparum malaria in Ghana.
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PMID:Relationship of hepcidin with parasitemia and anemia among patients with uncomplicated Plasmodium falciparum malaria in Ghana. 1797 60

Recent findings indicate a principal role for Hepcidin in iron homeostasis. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. Under normal conditions influx and efflux of iron from duodenal enterocytes is regulated by Ferroportin. Ferroportin is a Hepcidin binding protein expressed in duodenal enterocytes. Hepcidin is a peptide synthesised in the liver and is the main regulator of iron homeostasis. It is a defensin like protein and exhibits anti-microbial and anti-fungal activity. The Hepcidin gene is principally expressed in hepatocytes but to a lesser extent in neutrophils and macrophages. Hereditary Haemochromatosis is caused by disruption of iron homeostasis due to mutations in the HFE gene (C282Y or H63D). Unrestricted uptake of iron by duodenal enterocytes causes iron overload which is the hallmark of the disease. Current thinking is that defective Hepcidin synthesis or defective iron-sensing mechanisms leading to Hepcidin deficiency is the cause of iron overload in HFE-Haemochromatosis. Thus HFE-Haemochromatosis has been described as an endocrine disease. Basal levels of Hepcidin appear to be normal in HFE-Haemochromatosis patients. This contradicts current theories of defective Hepcidin synthesis as the cause of Hereditary HFE-Haemochromatosis. We propose that the defect in HFE-Haemochromatosis is the loss of Hepcidin surge in response to intake of dietary iron and is not as a result of reduced synthesis.
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PMID:Defective release of Hepcidin not defective synthesis is the primary pathogenic mechanism in HFE-Haemochromatosis. 1805 40

Thalassemia associates anemia and iron overload, two opposite stimuli regulating hepcidin gene expression. We characterized hepatic hepcidin expression in 10 thalassemia major and 13 thalassemia intermedia patients. Hepcidin mRNA levels were decreased in the thalassemia intermedia group which presented both lower hemoglobin and higher plasma soluble transferrin receptor levels. There was no relationship between hepcidin mRNA levels and those of genes controlling iron metabolism, including HFE, hemojuvelin, transferrin receptor-2 and ferroportin. These results underline the role of erythropoietic activity on hepcidin decrease in thalassemic patients and suggest that mRNA modulations of other studied genes do not have a significant impact.
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PMID:Anemia in beta-thalassemia patients targets hepatic hepcidin transcript levels independently of iron metabolism genes controlling hepcidin expression. 1816 93

Meeting the iron requirements of infants and children is difficult, and supplementation or fortification of food with iron is often recommended. Although iron supplementation of infants and children with iron deficiency and iron-deficiency anemia may be beneficial, recent studies suggest that this may not be the case for those with adequate iron status, and adverse effects have been noted. The recent discoveries of proteins and peptides regulating iron absorption have enhanced our knowledge of iron metabolism in infants and children. Iron is taken up in the small intestine by divalent metal transporter-1 and is either stored by ferritin inside the mucosal cell or transported to the systemic circulation by ferroportin, while being oxidized by hephaestin to be incorporated into transferrin. Hepcidin, a small peptide synthesized by the liver, can sense iron stores and regulates iron transport by inhibition of ferroportin. However, regulation of iron transporters is immature in infants, possibly explaining the adverse effects of iron supplementation. Interactions among iron, vitamin A, zinc, and copper need to be considered when evaluating the effects of iron supplementation on infants and children.
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PMID:Iron metabolism in infants and children. 1829 87


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