title: 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.
authors.affiliation: Department of Molecular and Integrative Physiology and Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Anderson
authors.forename: Matthew
authors.initials: M
authors.lastname: Taylor
authors.forename: Xiang
authors.initials: X
authors.lastname: Xue
authors.forename: Sadeesh K
authors.initials: SK
authors.lastname: Ramakrishnan
authors.forename: Angelical
authors.initials: A
authors.lastname: Martin
authors.forename: Liwei
authors.initials: L
authors.lastname: Xie
authors.forename: Bryce X
authors.initials: BX
authors.lastname: Bredell
authors.forename: Sara
authors.initials: S
authors.lastname: Gardenghi
authors.forename: Stefano
authors.initials: S
authors.lastname: Rivella
authors.forename: Yatrik M
authors.initials: YM
authors.lastname: Shah
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015153:Blotting, Western; D005295:Ferrocyanides; D007413:Intestinal Mucosa / Q000378:metabolism*; D019190:Iron Overload / Q000209:etiology* / Q000378:metabolism; D008156:Luciferases; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D014157:Transcription Factors / Q000378:metabolism; D017086:beta-Thalassemia / Q000150:complications* / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D005295:Ferrocyanides; D008156:Luciferases; D014157:Transcription Factors; D000099162:Endothelial PAS Domain-Containing Protein 1; C110547:DMRT1 protein; C000170:ferric ferrocyanide
keywords: Epas1; HIF; Slc11a2; thalassemia