HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice

J Clin Invest. 2009 May;119(5):1159-66. doi: 10.1172/JCI38499. Epub 2009 Apr 6.


HIF transcription factors (HIF-1 and HIF-2) are central mediators of cellular adaptation to hypoxia. Because the resting partial pressure of oxygen is low in the intestinal lumen, epithelial cells are believed to be mildly hypoxic. Having recently established a link between HIF and the iron-regulatory hormone hepcidin, we hypothesized that HIFs, stabilized in the hypoxic intestinal epithelium, may also play critical roles in regulating intestinal iron absorption. To explore this idea, we first established that the mouse duodenum, the site of iron absorption in the intestine, is hypoxic and generated conditional knockout mice that lacked either Hif1a or Hif2a specifically in the intestinal epithelium. Using these mice, we found that HIF-1alpha was not necessary for iron absorption, whereas HIF-2alpha played a crucial role in maintaining iron balance in the organism by directly regulating the transcription of the gene encoding divalent metal transporter 1 (DMT1), the principal intestinal iron transporter. Specific deletion of Hif2a led to a decrease in serum and liver iron levels and a marked decrease in liver hepcidin expression, indicating the involvement of an induced systemic response to counteract the iron deficiency. This finding may provide a basis for the development of new strategies, specifically in targeting HIF-2alpha, to improve iron homeostasis in patients with iron disorders.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimicrobial Cationic Peptides / genetics
  • Basic Helix-Loop-Helix Transcription Factors / physiology*
  • Caco-2 Cells
  • Cation Transport Proteins / genetics
  • Cation Transport Proteins / metabolism
  • Cell Hypoxia / physiology
  • Cytochromes b / genetics
  • Duodenum / metabolism
  • Erythrocytes / chemistry
  • Erythrocytes / cytology
  • Gene Expression / genetics
  • Gene Expression Regulation / physiology*
  • Hemoglobins / analysis
  • Hepcidins
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
  • Intestinal Absorption / physiology*
  • Iron / blood
  • Iron / metabolism*
  • Iron Deficiencies
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Promoter Regions, Genetic / physiology
  • Protein Binding / genetics
  • Response Elements / physiology
  • Transcriptional Activation / physiology


  • Antimicrobial Cationic Peptides
  • Basic Helix-Loop-Helix Transcription Factors
  • Cation Transport Proteins
  • HAMP protein, human
  • Hamp protein, mouse
  • Hemoglobins
  • Hepcidins
  • Hif1a protein, mouse
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • metal transporting protein 1
  • solute carrier family 11- (proton-coupled divalent metal ion transporters), member 2
  • endothelial PAS domain-containing protein 1
  • Cytochromes b
  • Iron