Abstract
During iron deficiency, perturbations in copper homeostasis have frequently been documented. Previous studies in iron-deprived rats demonstrated that enterocyte and hepatic copper levels increase and a copper transporter (the Menkes Copper ATPase; Atp7a) is induced in the duodenal epithelium in parallel to iron transport-related genes (e.g. Dmt1, Dcytb, Fpn1). Moreover, two ferroxidase proteins involved in iron homeostasis, hephaestin expressed in enterocytes and ceruloplasmin, produced and secreted into blood by the liver, are copper-dependent enzymes. We thus aimed to test the hypothesis that Atp7a function is important for the copper-related compensatory response of the intestinal epithelium to iron deficiency. Accordingly, iron homeostasis was studied for the first time in mice expressing a mutant Atp7a protein with minimal activity (Brindled [MoBr /y]). Mutant mice were rescued by perinatal copper injections, and, after a 7–8 week recovery period, were deprived of dietary iron for 3 weeks (along with WT littermates). Adult MoBr /y mice displayed copper-deficiency anemia but had normal iron status; in contrast, iron-deprived MoBr /y mice were iron deficient and more severely anemic with partial amelioration of the copper-deficient phenotype. Intestinal iron absorption in both genotypes (WT and MoBr /y) increased ∼3-fold when mice consumed a low-iron diet and ∼6-fold when mice were concurrently bled. WT mice exhibited no alterations in copper homeostasis in response to iron deprivation or phlebotomy. Conversely, upregulation of iron absorption was associated with increased enterocyte and liver copper levels and serum ferroxidase (ceruloplasmin) activity in MoBr /y mice, typifying the response to iron deprivation in many mammalian species. We thus speculate that a copper threshold exists that is necessary to allow appropriate regulate of iron absorption. In summary, MoBr /y mice were able to adequately regulate iron absorption, but unlike in WT mice, concurrent increases in enterocyte and liver copper levels and serum ferroxidase activity may have contributed to maintenance of iron homeostasis.
Highlights
Iron is an essential trace mineral that serves as a cofactor for enzymes which mediate diverse biochemical reactions including oxygen delivery, energy metabolism and immunity
Overall body iron homeostasis is primarily controlled by absorption of dietary iron in the upper small bowel, as no regulated excretory pathways exist in mammals
Previous investigations have noted that copper influences iron homeostasis [1,2,3]
Summary
Iron is an essential trace mineral that serves as a cofactor for enzymes which mediate diverse biochemical reactions including oxygen delivery, energy metabolism and immunity. In many mammalian species, body copper levels increase [4,5], including in the intestinal mucosa [6], the liver [7] and in serum [8]. Upregulation of Atp7a is consistent with documented alterations in intestinal and body copper levels during iron deficiency. Atp7a could directly influence enterocyte or liver copper levels, potentially increasing expression or activity of the multi-copper FOXs. Our approach was to utilize Brindled (MoBr/y) mice, which have a 6 base-pair deletion in the Atp7a gene [17], resulting in a protein with significantly reduced functional activity [18]. Unlike the situation in WT mice, where no alterations in copper levels were noted, increases in enterocyte and liver copper content and serum ferroxidase activity occurred concomitantly with enhanced iron absorption in mutant mice
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