title: Copper deficiency leads to anemia, duodenal hypoxia, upregulation of HIF-2α and altered expression of iron absorption genes in mice.
abstract: Iron and copper are essential trace metals, actively absorbed from the proximal gut in a regulated fashion. Depletion of either metal can lead to anemia. In the gut, copper deficiency can affect iron absorption through modulating the activity of hephaestin - a multi-copper oxidase required for optimal iron export from enterocytes. How systemic copper status regulates iron absorption is unknown. Mice were subjected to a nutritional copper deficiency-induced anemia regime from birth and injected with copper sulphate intraperitoneally to correct the anemia. Copper deficiency resulted in anemia, increased duodenal hypoxia and Hypoxia inducible factor 2α (HIF-2α) levels, a regulator of iron absorption. HIF-2α upregulation in copper deficiency appeared to be independent of duodenal iron or copper levels and correlated with the expression of iron transporters (Ferroportin - Fpn, Divalent Metal transporter - Dmt1) and ferric reductase - Dcytb. Alleviation of copper-dependent anemia with intraperitoneal copper injection resulted in down regulation of HIF-2α-regulated iron absorption genes in the gut. Our work identifies HIF-2α as an important regulator of iron transport machinery in copper deficiency.
authors.affiliation: INSERM, U1016, Institut Cochin, Paris, France.
authors.forename: Pavle
authors.initials: P
authors.lastname: Matak
authors.forename: Sara
authors.initials: S
authors.lastname: Zumerle
authors.forename: Maria
authors.initials: M
authors.lastname: Mastrogiannaki
authors.forename: Souleiman
authors.initials: S
authors.lastname: El Balkhi
authors.forename: Stephanie
authors.initials: S
authors.lastname: Delga
authors.forename: Jacques R R
authors.initials: JR
authors.lastname: Mathieu
authors.forename: François
authors.initials: F
authors.lastname: Canonne-Hergaux
authors.forename: Joel
authors.initials: J
authors.lastname: Poupon
authors.forename: Paul A
authors.initials: PA
authors.lastname: Sharp
authors.forename: Sophie
authors.initials: S
authors.lastname: Vaulont
authors.forename: Carole
authors.initials: C
authors.lastname: Peyssonnaux
mesh_terms: D000042:Absorption / Q000187:drug effects / Q000235:genetics; D000740:Anemia / Q000188:drug therapy / Q000209:etiology*; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D015687:Cell Hypoxia / Q000187:drug effects; D003300:Copper / Q000008:administration & dosage / Q000172:deficiency* / Q000494:pharmacology / Q000627:therapeutic use; D015536:Down-Regulation / Q000187:drug effects; D004386:Duodenum / Q000187:drug effects / Q000473:pathology*; D005260:Female; D007274:Injections, Intraperitoneal; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015854:Up-Regulation / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D003300:Copper; D007501:Iron; D000099162:Endothelial PAS Domain-Containing Protein 1
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