期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 110, 期 50, 页码 E4922-E4930出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1314197110
关键词
thalassemia; HIF; Epas1; Slc11a2
资金
- Rackham predoctoral fellowship
- National Institutes of Health [CA148828, DK095201]
- University of Michigan Gastrointestinal Peptide Center
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-2 alpha (HIF2 alpha) 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 HIF2 alpha. 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 alpha/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 alpha signaling is critical for progressive iron overload in beta-thalassemia and may be a novel therapeutic target in several anemic iron-overload disorders.
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