Downregulation of hepcidin and haemojuvelin expression in the hepatocyte cell‐line HepG2 induced by thalassaemic sera

Weizer-Stern, Orly; Adamsky, Konstantin; Amariglio, Ninette; Levin, Carina; Koren, Ariel; Breuer, William; Rachmilewitz, Eliezer A.; Breda, Laura; Rivella, Stefano; Cabantchik, Z. Ioav; Rechavi, Gideon

doi:10.1111/j.1365-2141.2006.06258.x

Cited by 72 publications

(54 citation statements)

References 49 publications

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“…Recently, we were able to show that the level of plasma soluble transferrin receptor, greatly increased both in iron deficiency and in ineffective erythropoiesis, does not modulate hepcidin expression [13]. On the other hand, it has recently been suggested that plasma from thalassemic patients has a negative effect on hepcidin levels in HepG2 cells [14]. It may be that soluble hemojuvelin, which has been shown to be present in the plasma, acts as a regulator by inhibiting ligation of the receptor for BMPs [15,16].…”

Section: The Central Role Of Hepcidinmentioning

confidence: 98%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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There are many forms of iron storage disease, some hereditary and some acquired. The most common of the hereditary forms is HFE-associated hemochromatosis, and it is this disorder that is the main focus of this presentation. The body iron content is regulated by controlling absorption, and studies in the past decade have clarified, in part, how this regulation functions. A 25 amino acid peptide hepcidin is upregulated by iron and by inflammation, and it inhibits iron absorption and traps iron in macrophages by binding to and causing degradation of the iron transport protein ferroportin. Most forms of hemochromatosis results from dysregulation of hepcidin or defects of hepcidin or ferroportin themselves.Hereditary hemochromatosis was once considered to be very rare, but in the 1970s and 1980s, with the introduction of better diagnostic tests, it became to be considered the most common disease of Europeans. Controlled epidemiologic studies carried out in the last decade have shown, however, the disease itself actually is rare, and it is only the genotype and associated biochemical changes that are common. We do not understand why only a few homozygotes develop severe disease. It now seems unlikely that there are important modifying genes, and although alcohol is known to have some effect, excess drinking probably plays only a modest role in determining the hemochromatosis phenotype.Hereditary hemochromatosis is readily treated by phlebotomy. Secondary forms of the disease require chelation therapy, and the recent introduction of effective oral chelating agents is an important step forward in treating patients with disorders in which iron overload often proves to be fatal, such as thalassemia, myelodysplastic anemias, and dyserythropoietic anemias.While much has been learned about the regulation of iron homeostasis in the past decade, many mysteries remain and represent challenges that will keep us occupied for years to come.It is a great honor for me to present this lecture in memory of my good friend Bracha Ramot. It is because this lecture is in honor of Bracha that I do not feel the least bit uncomfortable speaking about iron storage diseases in a symposium entitled "Genomics and Molecular Biology of Hematopoietic Malignancies". I know that had it been possible to ask her whether this might be appropriate Bracha would have said: "Of course, Ernie. Talk about whatever you want to". That was her way. And, of course, Bracha was no stranger to iron metabolism. She was scientifically broad, a Renaissance hematologist. A MEDLINE search reveals 261 publications by Bracha and eight of those deal with iron --iron in thalassemia, iron in sideroblastic anemia, and iron in iron deficiency anemia.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable...

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Section: The Central Role Of Hepcidinmentioning

confidence: 98%

Iron storage disease: Facts, fiction and progress

Beutler

2007

Blood Cells, Molecules, and Diseases

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“…Firstly, GDF15 has been shown to suppress hepcidin expression in cultured hepatocytes, and secondly, it circulates at extremely high levels in patients with beta thalassemia, potentially explaining their inappropriate hepcidin suppression in spite of iron overload. 25,26 This hypothesis was strengthened by the recent discovery that iron depletion in vitro induces GDF15 expression, and that infusion of the iron chelator deferoxamine increases plasma GDF15 in humans. 27 In our study, a modest but significant diurnal pattern to GDF15 was observed, with levels increasing slightly during each day, but the pattern remained constant during the week ( Figure 1E; the rise towards the end of day 3, which appears to be exaggerated, is not significantly different from day 1).…”

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confidence: 95%

Erythropoietin administration in humans causes a marked and prolonged reduction in circulating hepcidin

Ashby

Gale²,

Busbridge³

et al. 2009

Haematologica

174

136

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“…17 Sera from these patients decreased hepcidin expression in human hepatoma cell cultures, to an unexpectedly higher degree in TM. 18 In a recent study, hepcidin mRNA levels from the liver of TM patients were inversely correlated to serum levels of erythropoietin and trasferrin receptor, indicating that the down-regulation of hepcidin is proportional to the increase of erythropoietic activity.…”

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confidence: 99%