To avoid iron deficiency and overload, iron availability is tightly regulated at both the cellular and systemic levels. The liver peptide hepcidin controls iron flux to plasma from enterocytes and macrophages through degradation of the cellular iron exporter ferroportin.
The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle.
Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia.
Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.Introduction Iron is essential for multiple cell functions, but is also potentially deleterious because of its ability to generate free oxygen radicals.
Due to the absence of an active excretory mechanism, iron balance in mammals is maintained by limiting its intestinal uptake and by continuously recycling and reusing cellular iron. Multiple safety mechanisms, such as binding to chaperone proteins, storage in ferritin, and export through ferroportin (FPN), protect cells from free iron toxicity. The mechanisms of cellular iron handling are summarized in Figure 1. Iron is used in mitochondria for heme synthesis and iron sulfur cluster biogenesis. There is increasing interest in the latter pathway because iron sulfur clusters are prosthetic groups for key enzymes of DNA duplication, repair, and epigenetics.
Iron-regulatory proteins (IRPs) and hepcidin exert iron homeostatic control at the cell and systemic levels, respectively.1 Disruption of iron control mechanisms leads to genetic iron disorders and may also contribute to the pathophysiology of common pathologic conditions including inflammation, neurodegeneration, metabolic disorders, and cancer. At the cellular level, IRP1 and IRP2 orchestrate the coordinated expression of iron importers (transferrin receptor 1 [TFR1] and divalent metal transporter 1 [DMT1]) and of storage (ferritin light and heavy chains) and export (FPN) proteins. IRPs regulate their targets posttranscriptionally by binding to special stem loop elements in the untranslated regions of mRNA-encoding proteins involved in iron metabolism; binding activity is high in iron deficiency and hypoxia and is suppressed by iron and oxygen (for review, see Hentze et al1).
Recently, differential target specificity of the 2 IRPs has been identified, with IRP1 specifically controlling the hypoxia mediator HIF2-alpha2 and IRP2 controlling ferritin.3 Control of HIF2-alpha by IRP is one of the multiple links between iron and hypoxia. Undoubtedly, conditional deletion of either IRP in animal models will clarify other tissue- and IRP-specific roles.
At the systemic level, the liver peptide hepcidin regulates iron homeostasis by binding and degrading the sole cellular iron exporter FPN, which is highly expressed at the basolateral surface of duodenal enterocytes and on the cell membrane of macrophages. In this way, hepcidin restricts the amount of iron delivered to its plasma carrier transferrin.4 The concentration of both circulating and tissue iron provides distinct signals that modulate hepcidin.
The result is low hepcidin and active iron delivery to plasma in iron deficiency and high hepcidin with reduced iron flux to plasma in iron overload (Figure 2). How IRP-based and systemic regulatory pathways interconnect and work together in general iron homeostasis is only partially understood and is a subject of intensive investigation. Hepcidin up-regulation Hepcidin transcription in hepatocytes is dependent on the bone morphogenic protein (BMP)-SMAD signaling cascade (Figure 3A).1 BMP6 is the iron-related BMP receptor (BMPR) ligand in vivo, as shown by Bmp6 / mice, which have severe iron overload and very low hepcidin.5 In the liver,
BMP6 is mainly expressed in nonparenchymal cells such as sinusoidal endothelial and Kupffer cells.6 Binding of the ligand to BMPR complex on the hepatocyte surface triggers phosphorylation of SMAD proteins, which translocate to the nucleus to activate target genes including hepcidin (Figure 3A). In mice, liver-specific disruption of the BMPR ALK2 and ALK-3 or of SMAD4 molecule results in iron overload with low hepcidin.7 Hemojuvelin (HJV), a protein mutated in juvenile hemochromatosis type A (Table 1), is the essential BMP coreceptor in this pathway. In humans, its inactivation causes severe, early onset iron overload indistinguishable from hemochromatosis caused by inactivation of the hepcidin gene itself.8
Hemochromatosis type 1, 2 and 3 (Table 1) and their corresponding murine models show defective BPM signaling that results in hepcidin insufficiency. Whereas the function of membrane-HJV
The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle.
Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia.
Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.Introduction Iron is essential for multiple cell functions, but is also potentially deleterious because of its ability to generate free oxygen radicals.
Due to the absence of an active excretory mechanism, iron balance in mammals is maintained by limiting its intestinal uptake and by continuously recycling and reusing cellular iron. Multiple safety mechanisms, such as binding to chaperone proteins, storage in ferritin, and export through ferroportin (FPN), protect cells from free iron toxicity. The mechanisms of cellular iron handling are summarized in Figure 1. Iron is used in mitochondria for heme synthesis and iron sulfur cluster biogenesis. There is increasing interest in the latter pathway because iron sulfur clusters are prosthetic groups for key enzymes of DNA duplication, repair, and epigenetics.
Iron-regulatory proteins (IRPs) and hepcidin exert iron homeostatic control at the cell and systemic levels, respectively.1 Disruption of iron control mechanisms leads to genetic iron disorders and may also contribute to the pathophysiology of common pathologic conditions including inflammation, neurodegeneration, metabolic disorders, and cancer. At the cellular level, IRP1 and IRP2 orchestrate the coordinated expression of iron importers (transferrin receptor 1 [TFR1] and divalent metal transporter 1 [DMT1]) and of storage (ferritin light and heavy chains) and export (FPN) proteins. IRPs regulate their targets posttranscriptionally by binding to special stem loop elements in the untranslated regions of mRNA-encoding proteins involved in iron metabolism; binding activity is high in iron deficiency and hypoxia and is suppressed by iron and oxygen (for review, see Hentze et al1).
Recently, differential target specificity of the 2 IRPs has been identified, with IRP1 specifically controlling the hypoxia mediator HIF2-alpha2 and IRP2 controlling ferritin.3 Control of HIF2-alpha by IRP is one of the multiple links between iron and hypoxia. Undoubtedly, conditional deletion of either IRP in animal models will clarify other tissue- and IRP-specific roles.
At the systemic level, the liver peptide hepcidin regulates iron homeostasis by binding and degrading the sole cellular iron exporter FPN, which is highly expressed at the basolateral surface of duodenal enterocytes and on the cell membrane of macrophages. In this way, hepcidin restricts the amount of iron delivered to its plasma carrier transferrin.4 The concentration of both circulating and tissue iron provides distinct signals that modulate hepcidin.
The result is low hepcidin and active iron delivery to plasma in iron deficiency and high hepcidin with reduced iron flux to plasma in iron overload (Figure 2). How IRP-based and systemic regulatory pathways interconnect and work together in general iron homeostasis is only partially understood and is a subject of intensive investigation. Hepcidin up-regulation Hepcidin transcription in hepatocytes is dependent on the bone morphogenic protein (BMP)-SMAD signaling cascade (Figure 3A).1 BMP6 is the iron-related BMP receptor (BMPR) ligand in vivo, as shown by Bmp6 / mice, which have severe iron overload and very low hepcidin.5 In the liver,
BMP6 is mainly expressed in nonparenchymal cells such as sinusoidal endothelial and Kupffer cells.6 Binding of the ligand to BMPR complex on the hepatocyte surface triggers phosphorylation of SMAD proteins, which translocate to the nucleus to activate target genes including hepcidin (Figure 3A). In mice, liver-specific disruption of the BMPR ALK2 and ALK-3 or of SMAD4 molecule results in iron overload with low hepcidin.7 Hemojuvelin (HJV), a protein mutated in juvenile hemochromatosis type A (Table 1), is the essential BMP coreceptor in this pathway. In humans, its inactivation causes severe, early onset iron overload indistinguishable from hemochromatosis caused by inactivation of the hepcidin gene itself.8
Hemochromatosis type 1, 2 and 3 (Table 1) and their corresponding murine models show defective BPM signaling that results in hepcidin insufficiency. Whereas the function of membrane-HJV
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