Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency.
Iron deficiency and iron overload are among the most prevalent nutritional disorders worldwide. Duodenal cytochrome b (DcytB) and divalent metal transporter 1 (DMT1) are regulators of iron absorption. Their expression is increased during high systemic requirements for iron, but the molecular mechanisms that regulate DcytB and DMT1 expression are undefined. Hypoxia-inducible factor (HIF) signaling was induced in the intestine following acute iron deficiency in the duodenum, resulting in activation of DcytB and DMT1 expression and an increase in iron uptake. DcytB and DMT1 were demonstrated as direct HIF-2alpha target genes. Genetic disruption of HIF signaling in the intestine abolished the adaptive induction of iron absorption following iron deficiency, resulting in low systemic iron and hematological defects. These results demonstrate that HIF signaling in the intestine is a critical regulator of systemic iron homeostasis.
Shah
Yatrik M
YM
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Matsubara
Tsutomu
T
Ito
Shinji
S
Yim
Sun-Hee
SH
Gonzalez
Frank J
FJ
D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D003573:Cytochrome b Group / Q000378:metabolism; D004386:Duodenum / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D000090463:Iron Deficiencies; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010088:Oxidoreductases / Q000378:metabolism; D015398:Signal Transduction; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2
D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D027682:Cation Transport Proteins; D003573:Cytochrome b Group; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007501:Iron; D010088:Oxidoreductases; D000099162:Endothelial PAS Domain-Containing Protein 1; D000099236:Solute Carrier Family 11, Member 2; C422926:CYBRD1 protein, human