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

Proc Natl Acad Sci U S A. 2013 Dec 10;110(50):E4922-30. doi: 10.1073/pnas.1314197110. Epub 2013 Nov 26.


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.

Keywords: Epas1; HIF; Slc11a2; thalassemia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Blotting, Western
  • Ferrocyanides
  • Intestinal Mucosa / metabolism*
  • Iron Overload / etiology*
  • Iron Overload / metabolism
  • Luciferases
  • Mice
  • Real-Time Polymerase Chain Reaction
  • Transcription Factors / metabolism
  • beta-Thalassemia / complications*
  • beta-Thalassemia / metabolism


  • Basic Helix-Loop-Helix Transcription Factors
  • DMRT1 protein
  • Ferrocyanides
  • Transcription Factors
  • endothelial PAS domain-containing protein 1
  • Luciferases
  • ferric ferrocyanide