Relationship between Down-Regulation of Copper-Related Genes and Decreased Ferroportin Protein Level in the Duodenum of Iron-Deficient Piglets

Abstract

In mammals, 2 × 1012 red blood cells (RBCs) are produced every day in the bone marrow to ensure a constant supply of iron to maintain effective erythropoiesis. Impaired iron absorption in the duodenum and inefficient iron reutilization from senescent RBCs by macrophages contribute to the development of anemia. Ferroportin (Fpn), the only known cellular iron exporter, as well as hephaestin (Heph) and ceruloplasmin, two copper-dependent ferroxidases involved in the above-mentioned processes, are key elements of the interaction between copper and iron metabolisms. Crosslinks between these metals have been known for many years, but metabolic effects of one on the other have not been elucidated to date. Neonatal iron deficiency anemia in piglets provides an interesting model for studying this interplay. In duodenal enterocytes of young anemic piglets, we identified iron deposits and demonstrated increased expression of ferritin with a concomitant decline in both Fpn and Heph expression. We postulated that the underlying mechanism involves changes in copper distribution within enterocytes as a result of decreased expression of the copper transporter—Atp7b. Obtained results strongly suggest that regulation of iron absorption within enterocytes is based on the interaction between proteins of copper and iron metabolisms and outcompetes systemic regulation.

Anemia in Sports: A Narrative Review

“…Once inside the cell, the iron may be stored bound to ferritin or can be exported into the circulation through the transfer across the basolateral part of the enterocytes by the transport protein ferroportin; this protein is responsible for the export of iron into the circulation, both from enterocytes and macrophages. The export process also involves a copper-dependent ferroxidase, hephaestin, which converts ferrous iron back to ferric iron, thus connecting iron and copper absorption [ 23 , 24 , 25 , 26 , 27 , 28 ]. In the circulation, iron in the ferric state (Fe 3+ ) is bound to apo-transferrin, forming holo-transferrin.…”

Four Cases of Serum Copper Excess in Patients with Renal Anemia Receiving a Hypoxia-Inducible Factor-Prolyl Hydroxylase Inhibitor: A Possible Safety Concern

“…Although case 1 was the only case that showed excess level in both iron and copper, excess of both these metals was normalized after the discontinuation of roxadustat treatment. Second, ATP7A, an enterocyte copper exporter, is induced at transcriptional level by HIF-2α [ 4 ], and probably that it is involved in the export of copper ions to the bloodstream [ 7 , 12 ]. Thus, copper is likely redistributed to tissues including enterocytes, the liver, and the blood.…”