HIF-2α, but not HIF-1α, promotes iron absorption in mice
Maria Mastrogiannaki, … , Sophie Vaulont, Carole Peyssonnaux
Maria Mastrogiannaki, … , Sophie Vaulont, Carole Peyssonnaux
Published April 6, 2009
Citation Information: J Clin Invest. 2009;119(5):1159-1166. https://doi.org/10.1172/JCI38499.
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HIF-2α, but not HIF-1α, promotes iron absorption in mice

Abstract

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-1α was not necessary for iron absorption, whereas HIF-2α 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-2α, to improve iron homeostasis in patients with iron disorders.

Authors

Maria Mastrogiannaki, Pavle Matak, Brian Keith, M. Celeste Simon, Sophie Vaulont, Carole Peyssonnaux

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Figure 3

HIF-2α binds and trans-activates the human DMT1-1A promoter.

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HIF-2α binds and trans-activates the human DMT1-1A promoter. (A) Lef...
(A) Left: The HIF agonists L-Mim (500 μM), hydralazine (Hydr.; 150 μM), and desferrioxamine mesylate (DFO; 150 μM) induced DMT1-1A promoter–driven luciferase activity. Right: Caco-2/TC7 cells were transiently transfected with pGL3–DMT1-1A or pGL3-6XHRE vectors together with pcDNA3 empty vector as a control (C) or increasing concentrations of pcDNA3–HIF-1α and pcDNA3–HIF-2α. (B) Luciferase assay on Caco-2/TC7 cells transiently transfected with pGL3–DMT1-1A (WT) or serial truncated versions of DMT1-1A promoter (D5 to D1) in the presence of pcDNA3–HIF-2α at a 1:10 ratio. (C) Luciferase assay on Caco-2/TC7 cells transiently transfected with pGL3–DMT1-1A (WT) or pGL3–DMT1-1A mutated in each of the 5 HREs (HRE-1 mut to HRE-5 mut) in the presence of pcDNA3–HIF-2α at a 1:10 ratio. (D) Left: Western blot analysis of Caco-2/TC7 cells incubated or not (–) with L-Mim (500 μM). Lanes were run on the same gel but were noncontiguous, as indicated. Right: Quantification by real-time PCR of a ChIP experiment on Caco-2/TC7 cells incubated with or without L-Mim (500 μM). *P < 0.05, **P < 0.01, ***P < 0.001, unpaired Student’s t test.