Intestinal HIF2α 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 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 leading cause of iron overload. The mechanism of increased iron absorption in β-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2α (HIF2α) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of β-thalassemia and are essential for excess iron accumulation in mouse models of β-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2α. 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 HIF2α/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2α signaling is critical for progressive iron overload in β-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.

DOI: 10.1073/pnas.1314197110

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@article{Anderson2013IntestinalHP, title={Intestinal HIF2α promotes tissue-iron accumulation in disorders of iron overload with anemia.}, author={Erik R. Anderson and M P Taylor and Xiang Xue and Sadeesh Kumar Ramakrishnan and Angelical Martin and Liwei Xie and Bryce X. Bredell and Sara Gardenghi and Stefano Rivella and Yatrik M. Shah}, journal={Proceedings of the National Academy of Sciences of the United States of America}, year={2013}, volume={110 50}, pages={E4922-30} }