Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2 alpha and Altered Expression of Iron Absorption Genes in Mice

Pavle Matak, Sara Zumerle, Maria Mastrogiannaki, Souleiman El Balkhi, Stephanie Delga, Jacques R. R. Mathieu, Francois Canonne-Hergaux, Joel Poupon, Paul A. Sharp, Sophie Vaulont, Carole Peyssonnaux*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Citations (Scopus)

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 2 alpha (HIF-2 alpha) levels, a regulator of iron absorption. HIF-2 alpha 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-2 alpha-regulated iron absorption genes in the gut. Our work identifies HIF-2 alpha as an important regulator of iron transport machinery in copper deficiency.

Original languageEnglish
Article numbere59538
Number of pages9
JournalPL o S One
Volume8
Issue number3
DOIs
Publication statusPublished - 28 Mar 2013

Keywords

  • WILSON-DISEASE
  • DIETARY IRON
  • BRAIN IRON
  • IN-VITRO
  • METABOLISM
  • HEPHAESTIN
  • PROTEINS
  • RATS
  • CERULOPLASMIN
  • FERROPORTIN

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