The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation

Nicolas, Gaël; Chauvet, Caroline; Viatte, Lydie; Danan, Jean Louis; Bigard, Xavier; Devaux, Isabelle; Beaumont, Carole; Kahn, Axel; Vaulont, Sophie

doi:10.1172/jci200215686

Cited by 391 publications

(559 citation statements)

References 14 publications

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“…1a) compared to control mice. Conversely, and in agreement with previously-reported data [15], expression of the iron regulator hepcidin, used here as a control for the treatments, was reduced by 80% in the anemic mice (Fig. 1b).…”

Section: Lcn2 Expression Is Induced By Acute Anemiasupporting

confidence: 93%

Anemia upregulates lipocalin 2 in the liver and serum

Jiang

Constante

Santos

2008

Blood Cells, Molecules, and Diseases

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Lipocalin 2 (Lcn2), a mammalian protein that is expressed and secreted in various pathologic states, binds siderophores, which are high-affnity iron chelators. Besides its role in limiting iron availability to pathogens in the setting of bacterial infection, Lcn2:siderophore complexes can also deliver iron to cells. In this study, we examined Lcn2 regulation in the liver of mice in situations of increased iron utilization, namely, during anemia. Anemia induced by phlebotomy, iron deprivation, or phenylhydrazine treatment was associated with upregulation of Lcn2 gene expression in the liver and elevation of serum Lcn2 protein levels. We further explored the participation of several factors known to co-occur during anemia, including hypoxia, changes in iron levels, and erythropoietic drive, in the regulation of Lcn2 by anemia. We found that hypoxia, but not iron or erythropoietin, caused an induction of Lcn2 expression. The upregulation of Lcn2 levels by anemia and hypoxia, which is not directly mediated by iron or erythropoietin, suggests a possible physiological role for Lcn2 during increased iron utilization and mobilization from stores.

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Section: Lcn2 Expression Is Induced By Acute Anemiasupporting

confidence: 93%

Anemia upregulates lipocalin 2 in the liver and serum

Jiang

Constante

Santos

2008

Blood Cells, Molecules, and Diseases

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“…Erythropoiesis itself is a known negative regulator of the iron regulatory hormone hepcidin (Hamp) [2,3]. Although the exact molecular details of this regulation are not well understood, it is believed that the erythroid compartment releases a soluble factor which limits the production of Hamp in the liver [4].…”

Section: Introductionmentioning

confidence: 99%

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

et al. 2016

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Iron metabolism and erythropoiesis are inherently interlinked physiological processes. Regulation of iron metabolism is mediated by the iron-regulatory hormone hepcidin. Hepcidin limits the amount of iron released into the blood by binding to and causing the internalization of the iron exporter, ferroportin. A number of molecules and physiological stimuli, including erythropoiesis, are known to regulate hepcidin. An increase in erythropoietic demand decreases hepcidin, resulting in increased bioavailable iron in the blood. Transferrin receptor 2 (TFR2) is involved in the systemic regulation of iron metabolism. Patients and mice with mutations in TFR2 develop hemochromatosis due to inappropriate hepcidin levels relative to body iron. Recent studies from our laboratory and others have suggested an additional role for TFR2 in response to iron-restricted erythropoiesis. These studies used mouse models with perturbed systemic iron metabolism: anemic mice lacking matriptase-2 and Tfr2, or bone marrow transplants from iron-loaded Tfr2 null mice. We developed a novel transgenic mouse model which lacks Tfr2 in the hematopoietic compartment, enabling the delineation of the role of Tfr2 in erythroid development without interfering with its role in systemic iron metabolism. We show that in the absence of hematopoietic Tfr2 immature polychromatic erythroblasts accumulate with a concordant reduction in the percentage of mature erythroid cells in the spleen and bone marrow of anemic mice. These results demonstrate that erythroid Tfr2 is essential for an appropriate erythropoietic response in iron-deficient anemia. These findings may be of relevance in clinical situations in which an immediate and efficient erythropoietic response is required.

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“…In iron deficient states, hepcidin expression is negatively regulated by hypoxia and erythopoietic signals [5]. In the absence of hepcidin, ferroportin is maintained on the basolateral surface of enterocytes allowing for the absorption of dietary iron.…”

Section: Introductionmentioning

confidence: 99%

“…Iron is exported out of macrophages via ferroportin to be utilized for erythropoiesis. Positive regulators of hepcidin, leading to reduced ferroportin and decreased availability of iron, include increased circulating iron and inflammatory cytokines [5]. It is believed that hepcidin plays a role in innate immunity by decreasing available iron for microbial use [6].…”

Section: Introductionmentioning

confidence: 99%

Peering into the future: Hepcidin testing

2013

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Hepcidin, a small 25 amino acid peptide, has been well established as the iron regulatory hormone. Its expression is upregulated in response to iron and inflammatory cytokines, and downregulated in anemic or hypoxic states. Hepcidin decreases iron export into the plasma by binding to and inducing the degradation of ferroportin, an iron channel located on macrophages and the basolateral surface of enterocytes. This leads to decreased absorption of parental iron by the enterocytes, reduced recycling of erythrocyte iron by macrophages, and increased iron stores in the hepatocytes. Although hepcidin assays are not currently approved for clinical use in the United States, there is much interest in the potential use of this biomarker for management of iron related medical conditions. This review briefly summarizes the current hepcidin test platforms under investigation and the challenges associated with development of a clinical assay for this biomarker. In addition, selected potential future applications hepcidin testing in the clinical setting are addressed. Am. J.

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The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation

Cited by 391 publications

References 14 publications

Anemia upregulates lipocalin 2 in the liver and serum

Anemia upregulates lipocalin 2 in the liver and serum

Hematopoietic deletion of transferrin receptor 2 in mice leads to a block in erythroid differentiation during iron‐deficient anemia

Peering into the future: Hepcidin testing

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