Copper deficiency has minimal impact on ferroportin expression or function

Abstract

Interactions between copper and iron homeostasis have been known since the nineteenth century when anemia in humans was first described due to copper limitation. However, the mechanism remains unknown. Intestinal and liver iron concentrations are usually higher following copper deficiency (CuD). This may be due to impaired function of the multicopper oxidases hephaestin or ceruloplasmin (Cp), respectively. However, iron retention could be due to altered ferroportin (Fpn), the essential iron efflux transporter in enterocytes and macrophages. Fpn mRNA is controlled partially by intracellular iron and IRE dependence. CuD should augment Fpn based on iron level. Some argue that Fpn stability is controlled partially by membrane ferroxidase (GPI-Cp). CuD should result in lower Fpn since GPI-Cp expression and function is reduced. Fpn turnover is controlled by hepcidin. CuD results in variable Hamp (hepcidin) expression. Fpn mRNA and protein level were evaluated following dietary CuD in rats and mice. To correlate with Fpn expression, measurements of tissue iron were conducted in several rodent models. Following CuD there was little change in Fpn mRNA. Previous work indicated that under certain circumstances Fpn protein was augmented in liver and spleen following CuD. Fpn levels in CuD did not correlate with either total iron or non-heme iron (NHI), as iron levels in CuD liver were higher and in spleen lower than copper adequate controls. Fpn steady state levels appear to be regulated by a complex set of factors. Changes in Fpn do not explain the anemia of CuD.

Loss of pdr-1/parkin influences Mn homeostasis through altered ferroportin expression in C. elegans

“…Moreover, as FPN has not been shown to export Cu, the decrease in Cu levels may be a secondary effect of lowered intracellular Fe due to increased Fe efflux. Fe-deficiency anaemia has been associated with copper deficiencies, though the mechanism remains unknown 45, 46 . Though future studies are needed to further elucidate FPN’s transport profile in C. elegans , the rescue of the pdr-1 mutant phenotype through FPN overexpression supports our hypothesis that metal dyshomeostasis in the background of pdr-1 loss may be due to alterations in transporter expression.…”

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

“…However, in our nutritional copper deficiency model (Figures 1, 2, 3), duodenal iron content was not significantly altered relative to the control levels, yet Hif-2α was significantly increased. Indeed a number of studies, across species, have shown that iron retention in the gut, (associated with copper deficiency due to a significant decrease in hephaestin feroxidase activity and thus iron export) is not always observed in copper deficiency [17], [37]–[39] and this provides evidence that cellular iron levels per se may not be the major determinant of HIF-2α protein levels.…”

Molecular Mediators Governing Iron-Copper Interactions

“…Copper deficiency in mice was shown to increase FPN1 mRNA expression, possibly by a transcriptional mechanism involving HIF2α (71). Another recent study, however, provided contradictory results (90). These authors showed that copper restriction of rats and mice had little effect on FPN1 expression or activity.…”