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Intestinal HIF2? promotes tissue-iron accumulation in disorders of iron overload with anemia.

ABSTRACT: Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including ?-thalassemia major, which is characterized by a defective ?-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In ?-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leading cause of iron overload. The mechanism of increased iron absorption in ?-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2? (HIF2?) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of ?-thalassemia and are essential for excess iron accumulation in mouse models of ?-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2?. In addition to repeated blood transfusions and increased iron absorption, chronic hemolysis is the major cause of tissue-iron accumulation in anemic iron-overload disorders caused by hemolytic anemia. Mechanistic studies in a hemolytic anemia mouse model demonstrated that loss of intestinal HIF2?/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2? signaling is critical for progressive iron overload in ?-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

SUBMITTER: Anderson ER

PROVIDER: S-EPMC3864280 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia.

Anderson Erik R ER Taylor Matthew M Xue Xiang X Ramakrishnan Sadeesh K SK Martin Angelical A Xie Liwei L Bredell Bryce X BX Gardenghi Sara S Rivella Stefano S Shah Yatrik M YM

Proceedings of the National Academy of Sciences of the United States of America 20131126 50

Several distinct congenital disorders can lead to tissue-iron overload with anemia. Repeated blood transfusions are one of the major causes of iron overload in several of these disorders, including β-thalassemia major, which is characterized by a defective β-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In β-thalassemia intermedia, which does not require blood transfusion for survival, hyperabsorption of iron is the leadin ...[more]

PMID: 24282296

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Project description:Hereditary iron overload includes several disorders characterized by iron accumulation in tissues, organs, or even single cells or subcellular compartments. They are determined by mutations in genes directly involved in hepcidin regulation, cellular iron uptake, management and export, iron transport and storage. Systemic forms are characterized by increased serum ferritin with or without high transferrin saturation, and with or without functional iron deficient anemia. Hemochromatosis includes five different genetic forms all characterized by high transferrin saturation and serum ferritin, but with different penetrance and expression. Mutations in HFE, HFE2, HAMP and TFR2 lead to inadequate or severely reduced hepcidin synthesis that, in turn, induces increased intestinal iron absorption and macrophage iron release leading to tissue iron overload. The severity of hepcidin down-regulation defines the severity of iron overload and clinical complications. Hemochromatosis type 4 is caused by dominant gain-of-function mutations of ferroportin preventing hepcidin-ferroportin binding and leading to hepcidin resistance. Ferroportin disease is due to loss-of-function mutation of SLC40A1 that impairs the iron export efficiency of ferroportin, causes iron retention in reticuloendothelial cell and hyperferritinemia with normal transferrin saturation. Aceruloplasminemia is caused by defective iron release from storage and lead to mild microcytic anemia, low serum iron, and iron retention in several organs including the brain, causing severe neurological manifestations. Atransferrinemia and DMT1 deficiency are characterized by iron deficient erythropoiesis, severe microcytic anemia with high transferrin saturation and parenchymal iron overload due to secondary hepcidin suppression. Diagnosis of the different forms of hereditary iron overload disorders involves a sequential strategy that combines clinical, imaging, biochemical, and genetic data. Management of iron overload relies on two main therapies: blood removal and iron chelators. Specific therapeutic options are indicated in patients with atransferrinemia, DMT1 deficiency and aceruloplasminemia.

Dataset Information

Intestinal HIF2? promotes tissue-iron accumulation in disorders of iron overload with anemia.

Publications

Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia.

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