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

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

Author information

1
Department of Molecular and Integrative Physiology and Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.

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.

KEYWORDS:

Epas1; HIF; Slc11a2; thalassemia

PMID:
24282296
PMCID:
PMC3864280
DOI:
10.1073/pnas.1314197110
[Indexed for MEDLINE]
Free PMC Article

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