The molecular basis of ferroportin-linked hemochromatosis

Domenico, Ivana De; Ward, Diane McVey; Nemeth, Elizabeta; Vaughn, Michael B.; Musci, Giovanni; Ganz, Tomas; Kaplan, Jerry

doi:10.1073/pnas.0503804102

Cited by 206 publications

(243 citation statements)

References 27 publications

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“…Recently, hepcidin was reported to bind to the transmembrane iron exporter ferroportin 21,22 which is present on macrophages and the basolateral site of enterocytes ( Figure 1B and C), but also in hepatocytes. It has been demonstrated in vitro that hepcidin induces the internalization and degradation of ferroportin.…”

Section: Mechanism Of Hepcidin Activitymentioning

confidence: 97%

Hepcidin: from discovery to differential diagnosis

Kemna¹,

Tjalsma²,

Willems³

et al. 2008

Haematologica

267

186

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Although iron is essential for living organisms to survive, its reactive properties require strict regulation in order to prevent toxic effects. Hepcidin, a liver produced peptide hormone, is thought to be the central regulator of body iron metabolism. Its production is mainly controlled by the erythropoietic activity of the bone-marrow, the amount of circulating and stored body iron, and inflammation. Recent reports, however, provide new hypotheses on how hepcidin might exert its regulatory function. Although hepcidin was first discovered in human urine and serum, most of our understanding of hepcidin regulation and action comes from in vitro and mice studies that often use hepcidin mRNA expression as a read out. The difficulties in carrying out studies in humans have mostly been due to the lack of suitable hepcidin assay. The recent development of assays to measure hepcidin in serum and urine has offered new opportunities to study hepcidin regulation in humans. However, for the moment, only a small number of laboratories are able to perform these assays. The aim of this review is to discuss insights into hepcidin regulation obtained from recent clinical studies in the light of findings from in vitro and mice studies. Ongoing studies in humans should provide us with more information on the etiology of iron metabolism disorders in order to create new therapeutic strategies and improve differential diagnosis protocols for these diseases.

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Section: Mechanism Of Hepcidin Activitymentioning

confidence: 97%

Hepcidin: from discovery to differential diagnosis

Kemna¹,

Tjalsma²,

Willems³

et al. 2008

Haematologica

267

186

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“…Very high levels of ferritin may be found in hemochromatosis type 4 or ferroportin disease which does not result from impaired hepcidin but rather from heterozygous mutations of the hepcidin receptor ferroportin. 5 The disease is autosomal dominant and has a variable clinical phenotype. The true ferroportin disease (hemochromatosis type 4a in Table 1) is due to mutant proteins that are not correctly targeted to the cell surface and is characterized by macrophage iron accumulation, low/normal transferrin saturation and iron-restricted erythropoiesis.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 99%

Towards explaining "unexplained hyperferritinemia"

Camaschella¹,

Poggiali²

2009

Haematologica

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© F e r r a t a S t o r t i F o u n d a t i o nIron (NTBI), the toxic moiety of iron, responsible for liver damage and eventually damage to the heart, pancreas and pituitary gland. Very high levels of ferritin may be found in hemochromatosis type 4 or ferroportin disease which does not result from impaired hepcidin but rather from heterozygous mutations of the hepcidin receptor ferroportin. 5 The disease is autosomal dominant and has a variable clinical phenotype. The true ferroportin disease (hemochromatosis type 4a in Table 1) is due to mutant proteins that are not correctly targeted to the cell surface and is characterized by macrophage iron accumulation, low/normal transferrin saturation and iron-restricted erythropoiesis.6 A second form (hemochromatosis type 4b), due to mutant ferroportins that reach the cell surface but are resistant to hepcidin-induced internalization, 7 is characterized by hepatocyte iron accumulation and high transferrin saturation, as in hemochromatosis. The distinction is clinically relevant, because the true ferroportin disease seems not to be associated with clinical complications. These observations strengthen the relevance of assessing serum ferritin always in the context of transferrin saturation ( Figure 1).Ferritin is increased in iron overload secondary to chronic blood transfusions irrespective of the reason and also in the so called iron loading anemias, which include beta-thalassemia syndromes 8 and congenital sideroblastic or dyserythropoietic anemias, 9 characterized by high levels of ineffective erythropoiesis and low hepcidin production. All these conditions are usually well known from the patient's history and may be diagnosed by specific tests. Several methods such as magnetic resonance imaging (MRI) 10 or SQUID 11 have become available to non-invasively assess hepatic iron concentration: however, serial ferritin determinations remain a useful guide to assess iron overload and to monitor iron chelation therapy in these patients. 12Moderate increase of serum ferritin with normal/high transferrin saturation and mild/moderate liver iron accumulation may be common in chronic liver disorders, such as alcoholic liver disease and chronic viral hepatitis. These conditions require attention because iron may amplify the toxic effect of alcohol and viruses, accelerating the evolution towards fibrosis and cirrhosis. In porphyria cutanea tarda hyperferritinemia is a sign of iron overload (in some cases due to HFE mutations) 13 and, like alcohol and chronic hepatitis, is a trigger of porphyria attacks.In the metabolic syndrome (variable combination of hypertension, diabetes, hypertrigliceridemia, obesity, steatohepatitis or fatty liver) moderate elevation of ferritin is common, but usually ferritin levels are disproportionately high in comparison with iron stores, 14 whereas transferrin saturation is not increased.In recent years, new forms of inherited hyperferritinemia not associated with iron overload have been identified, adding new elements for differential diagnosis. A rare d...

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“…In contrast, there was no increase in ferritin when cells were transfected with a mutant Fpn [Fpn(V162-GFP)], which is unable to export metals because it is not targeted to the cell surface. 21 Our explanation for the decrease in ferritin levels in cells not expressing wild-type Fpn is that zinc induces endogenous Fpn expression resulting in iron export and concomitantly lowering ferritin. In cells transfected with wild-type Fpn, the level of expressed Fpn is so high that zinc-induced endogenous Fpn has little effect over the CMV-expressed Fpn.…”

mentioning

confidence: 98%

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

Troadec¹,

Ward²,

Lo³

et al. 2010

Blood

Self Cite

120

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IntroductionFerroportin (Fpn) is the only known mammalian iron exporter and plays an essential role in the entry of iron into plasma (for review, see Wessling-Resnick 1 and Wrighting and Andrews 2 ). Fpn is most highly expressed in cells that play a major role in iron acquisition: duodenal enterocytes, macrophages, hepatocytes and syncytial trophoblasts. Fpn, however, can be expressed on a wide variety of other cell types in response to heme 3,4 or iron. [5][6][7] Iron can regulate Fpn expression through transcriptional and translational mechanisms. Ferroportin1 (FPN1), the gene that encodes Fpn, contains a 5Ј iron-responsive element (IRE), which places its translation under the control of iron regulatory proteins. It is thought that the increased expression of Fpn by iron is a response to cellular iron load, as increased cytosolic iron would lead to increased iron export.FPN1 mRNA levels are also increased when cells are exposed to transition metals such as zinc, manganese, cadmium, copper, and other transition metals. 6 In both J774 cells and Caco cells, the increase in Fpn expression resulted in increased iron export. What is unclear, however, is the physiologic function of transition metal-induced expression of Fpn. Iron export in response to increased transition metals may protect cells from transition metal toxicity, perhaps by reducing the potential for iron-induced Fenton chemistry. Alternatively, Fpn might export other metals in addition to iron and thus increased expression of Fpn would directly protect cells from metal toxicity.In this study, we identify at least 1 mechanism by which transition metals induce Fpn expression. We show that zinc and cadmium can activate FPN1 transcription through the Metal Transcription Factor-1 (MTF-1). We also demonstrate that Fpn transports zinc and can protect cells from zinc toxicity. MethodsVector pcDNA3.1-mouse-MTF1-Flag was a gift from Dr G. K. Andrews. 8 We produced a chimera pcDNA3.1-mouse/human-MTF1-Flag by switching the mouse fragment with the human corresponding fragment between KpnI/FseI sites of mouse MTF1-Flag. To express an shRNA against mouse MTF-1, we inserted a double strand oligonucleotide targeting the gtacttcgccaccgctgta sequence of mouse MTF-1 into BamHI and EcoRI sites of pSIREN-DNR-DSRed (Clontech) according to manufacturer's instructions. The mouse/human chimera MTF-1 is resistant to shRNA against mouse MTF-1. The pGL3-control vector (Promega) was modified to perform the luciferase assay. The SV40 promoter was removed by HindIII/NheI digestion and the mouse Fpn promoter (starting at Ϫ2378, Ϫ1154, and Ϫ623 from the TATAA box) was amplified by polymerase chain reaction (PCR) and inserted using same restriction sites. The 5ЈIRE in the FPN1 promoter was deleted by BamHI/SamI digestion as described. 9 The putative metal-responsive elements (MREs) in the Fpn promoter in pGL3 were mutagenized by PCR to produce TCCAGCA*GA*AT*CT*CG and TGGAAGAA*TT*CG*AG (the consensus sequence is underlined, *mutagenized base). Fpn-green fluorescent protein (GFP) was car...

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The molecular basis of ferroportin-linked hemochromatosis

Abstract: hepcidin ͉ iron overload ͉ ferritin ͉ iron export

Cited by 206 publications

References 27 publications

Hepcidin: from discovery to differential diagnosis

Hepcidin: from discovery to differential diagnosis

Towards explaining "unexplained hyperferritinemia"

Induction of FPN1 transcription by MTF-1 reveals a role for ferroportin in transition metal efflux

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