| First Author | Anderson ER | Year | 2013 |
| Journal | Proc Natl Acad Sci U S A | Volume | 110 |
| Issue | 50 | Pages | E4922-30 |
| PubMed ID | 24282296 | Mgi Jnum | J:205514 |
| Mgi Id | MGI:5545692 | Doi | 10.1073/pnas.1314197110 |
| Citation | Anderson ER, et al. (2013) Intestinal HIF2alpha promotes tissue-iron accumulation in disorders of iron overload with anemia. Proc Natl Acad Sci U S A 110(50):E4922-30 |
| abstractText | 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 beta-thalassemia major, which is characterized by a defective beta-globin gene. In this state, hyperabsorption of iron is also observed and can significantly contribute to iron overload. In beta-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 beta-thalassemia is unclear. We definitively demonstrate, using genetic mouse models, that intestinal hypoxia-inducible factor-2alpha (HIF2alpha) and divalent metal transporter-1 (DMT1) are activated early in the pathogenesis of beta-thalassemia and are essential for excess iron accumulation in mouse models of beta-thalassemia. Moreover, thalassemic mice with established iron overload had significant improvement in tissue-iron levels and anemia following disruption of intestinal HIF2alpha. 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 HIF2alpha/DMT1 signaling led to decreased tissue-iron accumulation in the liver without worsening the anemia. These data demonstrate that dysregulation of intestinal hypoxia and HIF2alpha signaling is critical for progressive iron overload in beta-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders. |
