Molecular Regulation of The Menkes Copper ATPase (Atp7a) and Divalent Metal Transporter 1 (Dmt1) by Iron in Rat Duodenum and IEC‐6 Cells

Abstract

Iron transport-related genes are induced by iron-deficiency in the mammalian duodenum. We also noted very strong induction of genes related to intestinal copper homeostasis (Atp7a and metallothionein) during iron-deficiency, and intestinal and hepatic Cu-loading. Intestinal copper transport may thus be enhanced by iron deprivation; in fact, our preliminary studies support this supposition and we hypothesize that that Dmt1 and Atp7a play roles in this process. Importantly, 2 proteins involved in intestinal iron transport, hephaestin and ceruloplasmin, are copper-dependent ferroxidases. We further show that Dmt1 protein expression is very strongly induced and present in brush-border membrane (BBM) vesicles, while Atp7a protein levels are also dramatically increased and surprisingly present on both BB and basolateral membrane domains. We demonstrate that both Dmt1 and Atp7a are induced throughout the length of the GI tract. We have now developed IEC-6 cells as an in vitro model of intestinal iron and copper transport. Dmt1 and Atp7a are strongly induced by iron chelation in pre- and post-confluent cells, and membrane associated Atp7a protein expression is also greatly enhanced. Additional mechanistic studies demonstrate that the induction of Dmt1 and Atp7a are likely via distinct molecular mechanisms. Overall, these studies have described novel molecular events in the intestines of iron-deficient rats and IEC-6 cells that may have relevance to understanding the mechanisms involved in upregulation of iron transport during deficient states.