Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P02794 (ferritin)
 17,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepcidin is a liver-made peptide proposed to be a central regulator of intestinal iron absorption and iron recycling by macrophages. In animal models, hepcidin is induced by inflammation and iron loading, but its regulation in humans has not been studied. We report that urinary excretion of hepcidin was greatly increased in patients with iron overload, infections, or inflammatory diseases. Hepcidin excretion correlated well with serum ferritin levels, which are regulated by similar pathologic stimuli. In vitro iron loading of primary human hepatocytes, however, unexpectedly down-regulated hepcidin mRNA, suggesting that in vivo regulation of hepcidin expression by iron stores involves complex indirect effects. Hepcidin mRNA was dramatically induced by interleukin-6 (IL-6) in vitro, but not by IL-1 or tumor necrosis factor alpha (TNF-alpha), demonstrating that human hepcidin is a type II acute-phase reactant. The linkage of hepcidin induction to inflammation in humans supports its proposed role as a key mediator of anemia of inflammation.
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PMID:Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. 1243 76

Experimental data suggest the antimicrobial peptide hepcidin as a central regulator in iron homeostasis. In this study, we characterized the expression of human hepcidin in experimental and clinical iron overload conditions, including hereditary hemochromatosis. Using quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), we determined expression of hepcidin and the most relevant iron-related genes in liver biopsies from patients with hemochromatosis and iron-stain-negative control subjects. Regulation of hepcidin mRNA expression in response to transferrin-bound iron, non-transferrin-bound iron, and deferoxamine was analyzed in HepG2 cells. Hepcidin expression correlated significantly with serum ferritin levels in controls, whereas no significant up-regulation was observed in patients with hemochromatosis despite iron-overload conditions and high serum ferritin levels. However, patients with hemochromatosis showed an inverse correlation between hepcidin transcript levels and the serum transferrin saturation. Moreover, we found a significant correlation between hepatic transcript levels of hepcidin and transferrin receptor-2 irrespective of the iron status. In vitro data indicated that hepcidin expression is down-regulated in response to non-transferrin-bound iron. In conclusion, the presented data suggest a close relationship between the transferrin saturation and hepatic hepcidin expression in hereditary hemochromatosis. Although the causality is not yet clear, this interaction might result from a down-regulation of hepcidin expression in response to significant levels of non-transferrin-bound iron.
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PMID:Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. 1263 25

Hepcidin has been implicated as the iron stores regulator: a hepatic signaling molecule that regulates intestinal iron absorption by undefined mechanisms. The possibility that hepcidin regulates the expression of ferroportin 1 (FPT1), the basolateral iron transporter, was examined in rats after administration of LPS, an iron chelator, or His-tagged recombinant hepcidin (His-rHepc). In the liver, LPS stimulated a biphasic increase of hepcidin mRNA with peaks of mRNA at 6 and 36 h. Concurrently, hepatic FPT1 mRNA expression decreased to minimal level at 6 h and then increased with a peak at 24-36 h. LPS also induced biphasic changes in intestinal FPT1 mRNA expression, with decreased levels at 6 h and increased expression at 48 h. Whereas the initial decrease of FPT1 coincides with an LPS-induced decrease in serum iron, both intestinal and hepatic FPT1 expression recovered, whereas serum iron concentration continued to decrease for at least 24 h. Dietary iron ingestion increased intestinal ferritin protein production but did not reduce intestinal FPT1 mRNA expression. The iron chelator pyrrolidinedithiocarbamate (PDTC) stimulated hepatic hepcidin without suppressing intestinal FPT1 expression. In PDTC-treated rats, LPS stimulated no additional hepatic hepcidin expression but did increase intestinal FPT1 expression. Administration of HisrHepc induced significant reduction of intestinal FPT1 expression. Taken together, these data suggest that hepcidin mediates LPS-induced downregulation of intestinal FPT1 expression and that the hepcidin signaling pathway involves a PDTC-sensitive step.
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PMID:Hepcidin regulation of ferroportin 1 expression in the liver and intestine of the rat. 1459 44

The anaemia of chronic disease (ACD) is a common haematologic syndrome characterized by hypoferraemia with adequate reticuloendothelial iron stores. Frequently, serum ferritin concentration in these patients is elevated. The pathogenesis of ACD involves abnormalities in red cell survival, the erythropoietic response to anaemia, and in iron metabolism. Hepcidin is an antibacterial protein produced in the liver which can be found in blood or urine, and which participates in host defense. Recent studies have demonstrated that hepcidin is a key regulator of iron balance in the intestinal mucosa, and that abnormalities in hepcidin gene expression are associated with clinical abnormalities in iron parameters and, in some cases, with anaemia. Hepcidin is an acute-phase reacting protein, and it has been suggested that hepcidin is the key mediator of ACD. Investigation of hepcidin production in either serum or urine demonstrates a strong correlation with serum ferritin concentration. Differences between the hepcidin concentrations observed in ACD (or syndromes resembling ACD) and those observed in iron deficiency may depend on the definition used for the anaemia syndrome. It seems very likely that hepcidin is a major contributor to iron abnormalities characteristic of ACD; whether it contributes to the pathogenesis of the syndrome in a broader sense remains to be determined by further investigation.
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PMID:Hepcidin and anaemia. 1550 50

Hepcidin is a cytokine-induced antibacterial protein which is produced in the liver, circulates in the blood, and is excreted in the urine. It is a major regulator of iron balance in the intestinal mucosa, and appears to have a significant role in the pathogenesis of haemochromatosis and related disorders. Hepcidin appears to be a major contributor to the hypoferraemia associated with inflammation. Serum ferritin concentration is strongly correlated with hepcidin protein levels in either urine or serum, and certain patients with hepatic adenomas exhibit a microcytic, hypoferraemic hepcidin-dependent anaemia. For these reasons, it has been proposed that hepcidin is a primary factor in the pathogenesis of the anaemia of chronic disease (ACD), a cytokine-mediated anaemia commonly encountered in clinical practice and characterized by hypoferraemia with adequate reticuloendothelial iron stores. However, the pathogenetic basis of ACD is not entirely due to changes in iron metabolism, but also involves abnormalities in red cell survival and the erythropoietic response to anaemia. In this review, the evidence for involvement of hepcidin as a major mediator of ACD is evaluated. Hepcidin appears to be a major factor in the systemic iron abnormalities seen in ACD; whether it contributes to the other aspects of the pathogenesis of the syndrome requires further investigation.
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PMID:Hepcidin and cytokines in anaemia. 1576 74

The cellular iron exporter ferroportin 1 is expressed in both the duodenum and in cells of the mononuclear phagocyte system. Expression of ferroportin 1 protein on the cell surface is regulated by the interaction of ferroportin 1 with hepcidin. Hepcidin treatment of cells results in internalization and lysosomal degradation of cell surface ferroportin 1. Recently, ferroportin 1 mutations leading to hemochromatosis (HFE4) have been identified. HFE4 differs from classical hemochromatosis in that there is a greater amount of macrophage iron sequestration. The data presented here demonstrate that HFE4 mutations are heterogeneous in their effects on protein function. Some mutations result in loss of function with partial protein sequestration in the ER. Others are indistinguishable from native ferroportin 1 and have a similar ability to deplete transfected cells of iron as evidenced by activation of the iron-response proteins and cellular ferritin depletion. Significantly, all mutants appear to be unresponsive to hepcidin and do not demonstrate the expected internalization on exposure to hepcidin. The clinical phenotypes observed in patients may be secondary to cell-type-specific defects in hepcidin-mediated inhibition of ferroportin 1 expression.
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PMID:Functional consequences of ferroportin 1 mutations. 1593 10

Hepcidin is a small peptide that acts as a regulator of systemic iron homeostasis. To study some of its functional properties, a synthetic cDNA for the minimal, 20-amino-acid, form of human hepcidin was cloned into different constructs for expression in Escherichia coli. The fusion ferritin-hepcidin produced molecules retaining most of ferritin structural and functional properties, including ferroxidase and iron incorporation activities. However, it showed spectroscopic properties compatible with the presence of iron-sulfur complexes on the hepcidin moiety, which was buried into protein cavity. Similar complexes were reconstituted by in vitro incubation of the iron-free protein with iron and sulfide salts. Two other unrelated fusion products were constructed, which, when expressed in E. coli, formed insoluble aggregates retaining a large proportion of total bacterial iron. Analysis of the solubilized preparations showed them to contain iron-sulfur complexes. We concluded that the cysteine-rich hepcidin acts as an iron-sequestering molecule during expression in E. coli. This may have implications for the biological functions of this key protein of iron metabolism.
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PMID:Recombinant human hepcidin expressed in Escherichia coli isolates as an iron containing protein. 1600 82

Hepcidin is the principal iron-regulatory hormone. It acts by binding to the iron exporter ferroportin, inducing its internalization and degradation, thereby blocking cellular iron efflux. The bioactive 25 amino acid (aa) peptide has a hairpin structure stabilized by 4 disulfide bonds. We synthesized a series of hepcidin derivatives and determined their bioactivity in a cell line expressing ferroportin-GFP fusion protein, by measuring the degradation of ferroportin-GFP and the accumulation of ferritin after peptide treatment. Bioactivity was also assayed in mice by the induction of hypoferremia. Serial deletion of N-terminal amino acids caused progressive decrease in activity which was completely lost when 5 N-terminal aa's were deleted. Synthetic 3-aa and 6-aa N-terminal peptides alone, however, did not internalize ferroportin and did not interfere with ferroportin internalization by native hepcidin. Deletion of 2 C-terminal aa's did not affect peptide activity. Removal of individual disulfide bonds by pairwise substitution of cysteines with alanines also did not affect peptide activity in vitro. However, these peptides were less active in vivo, likely because of their decreased stability in circulation. G71D and K83R, substitutions previously described in humans, did not affect hepcidin activity. Apart from the essential nature of the N-terminus, hepcidin structure appears permissive for mutations.
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PMID:The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. 1614 45

Most patients suffering from chronic infections, chronic inflammatory diseases, and some malignancies develop a mild to moderate anemia designated anemia of chronic disease or anemia of inflammation. Patients with this anemia have low serum iron, low to normal transferrin, and high to normal serum ferritin concentration. The anemia is caused by increased inflammatory cytokines, especially IL-6, inducing increased production of the iron-regulatory hormone hepcidin by hepatocytes. Hepcidin blocks the release of iron from macrophages, hepatocytes, and enterocytes, causing the characteristic hypoferremia associated with this anemia and iron-deprivation of the developing erythrocytes.
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PMID:Molecular pathogenesis of anemia of chronic disease. 1626 3

The liver performs three main functions in iron homeostasis. It is the major site of iron storage, it regulates iron traffic into and around the body through its production of the peptide hepcidin, and it is the site of synthesis of major proteins of iron metabolism such as transferrin and ceruloplasmin. Most of the iron that enters the liver is derived from plasma transferrin under normal circumstances, and transferrin receptors 1 and 2 play important roles in this process. In pathological situations, non-transferrin-bound iron, ferritin, and hemoglobin/haptoglobin and heme/hemopexin complexes assume greater importance in iron delivery to the organ. Iron is stored in the liver as ferritin and, with heavy iron loading, as hemosiderin. The liver can divest itself of iron through the plasma membrane iron exporter ferroportin 1, a process that also requires ceruloplasmin. Hepcidin can regulate this iron release through its interaction with ferroportin.
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PMID:Hepatic iron metabolism. 1631 36


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