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

TY - JOUR

T1 - Copper Deficiency Leads to Anemia, Duodenal Hypoxia, Upregulation of HIF-2 alpha and Altered Expression of Iron Absorption Genes in Mice

AU - Matak, Pavle

AU - Zumerle, Sara

AU - Mastrogiannaki, Maria

AU - El Balkhi, Souleiman

AU - Delga, Stephanie

AU - Mathieu, Jacques R. R.

AU - Canonne-Hergaux, Francois

AU - Poupon, Joel

AU - Sharp, Paul A.

AU - Vaulont, Sophie

AU - Peyssonnaux, Carole

PY - 2013/3/28

Y1 - 2013/3/28

N2 - 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.

AB - 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.

KW - WILSON-DISEASE

KW - DIETARY IRON

KW - BRAIN IRON

KW - IN-VITRO

KW - METABOLISM

KW - HEPHAESTIN

KW - PROTEINS

KW - RATS

KW - CERULOPLASMIN

KW - FERROPORTIN

U2 - 10.1371/journal.pone.0059538

DO - 10.1371/journal.pone.0059538

M3 - Article

SN - 1932-6203

VL - 8

JO - PL o S One

JF - PL o S One

IS - 3

M1 - e59538

ER -