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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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Research Article Gastroenterology

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

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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 1

Intestine-specific deletion of Hif1a and Hif2a.

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Intestine-specific deletion of Hif1a and Hif2a.
   
(A) Immunostaining f...
(A) Immunostaining for the hypoxic marker Hypoxyprobe in WT mouse duodenum (original magnification, ×100) and lung (original magnification, ×200). The control corresponds to the omission of primary antibody. (B) HIF-1αfl/fl and HIF-2αfl/fl mice (both floxed at exon 2) were bred with a transgenic strain expressing Cre recombinase under the control of the murine villin promoter. (C) Recombination efficiency for HIF-1αfl/fl and HIF-2αfl/fl alleles quantified by real-time PCR of genomic DNA isolated from the duodenum as described previously (30). n = 4 in each group. Hif1a and Hif2a mRNA levels in duodenum scrapings of vil-Cre+/HIF-1αfl/fl and vil-Cre+/HIF-2αfl/fl mice and WT littermates as determined by real-time PCR. n = 4 in each group. **P < 0.01, unpaired Student’s t test. (D) H&E staining of duodenum of a vil-Cre+/HIF-2αfl/fl mouse and a WT littermate (original magnification, ×200).
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