Copper supplementation reverses dietary iron overload-induced pathologies in mice

Abstract

Dietary iron overload in rodents impairs growth and causes cardiac hypertrophy, serum and tissue copper depletion, depression of serum ceruloplasmin (Cp) activity and anemia. Notably, increasing dietary copper content to ~25-fold above requirements prevents the development of these physiological perturbations. Whether copper supplementation can reverse these high-iron-related abnormalities has, however, not been established. The current investigation was thus undertaken to test the hypothesis that supplemental copper will mitigate negative outcomes associated with dietary iron loading. Weanling mice were thus fed AIN-93G-based diets with high (>100-fold in excess) or adequate (~80 ppm) iron content. To establish the optimal experimental conditions, we first defined the time course of iron loading, and assessed the impact of supplemental copper (provided in drinking water) on the development of high-iron-related pathologies. Copper supplementation (20 mg/L) for the last 3 weeks of a 7-week high-iron feeding period reversed the anemia, normalized serum copper levels and Cp activity, and restored tissue copper concentrations. Growth rates, cardiac copper concentrations and heart size, however, were only partially normalized by copper supplementation. Furthermore, high dietary iron intake reduced intestinal Cu absorption (~60%) from a transport solution provided to mice by oral, intragastric gavage. Copper supplementation of iron-loaded mice enhanced intestinalCu transport, thus allowing sufficient assimilation of dietary copper to correct many of the noted high-iron-related physiological perturbations. We therefore conclude that high- iron intake increases the requirement for dietary copper (to overcome the inhibition of intestinal copper absorption).

Molecular Insights Into Lysyl Oxidases in Cartilage Regeneration and Rejuvenation

“…Copper, an essential redox-active trace element, which is essential for most aerobic organisms (Tapiero et al, 2003;Solomon et al, 2014). Simultaneously, copper functions as a co-factor of various proteins and enzymes, including cytochrome C, superoxide dismutase, tyrosinase, ascorbate oxidase, lysyl oxidase, and amine oxidase, exhibiting diverse fundamental cellular functions in normal physiology, including energy generation, iron acquisition, oxygen transportation, cellular metabolism, peptide hormone maturation, blood clotting, neurotransmitter biosynthesis, and intracellular signal transduction (Huffman and O'Halloran, 2001;Hamza and Gitlin, 2002;Kim et al, 2008;Turski et al, 2012;Grubman and White, 2014;Wang et al, 2018;Miller et al, 2019). Generally, copper is able to exist in two oxidation states in the body of mammalians: Cu + and Cu 2+ (Lin and Kosman, 1990;Pushie et al, 2007;Solomon et al, 2014).…”

Dietary Iron Intake in Excess of Requirements Impairs Intestinal Copper Absorption in Sprague Dawley Rat Dams, Causing Copper Deficiency in Suckling Pups

“…Here, our intent was to test the hypothesis that high intake of dietary iron in previously ID rat dams would have pathological outcomes for suckling pups. This investigation builds logically on our previous work in rats and mice demonstrating that iron intake at levels ≈5-fold above requirements causes copper depletion and associated pathological outcomes [ 13 , 14 , 15 , 16 ]. Although we are investigating the effect of high enteral iron on copper absorption, it is also important to consider possible influences of high iron on the absorption of other minerals (e.g., zinc).…”

“…Additional recent investigations supported these postulates, as increases in dietary iron resulted in copper deficiency-related pathological outcomes in adolescent rats [ 13 , 14 ] and mice [ 15 ]. Copper supplementation of mice consuming a high-iron diet prevented the development of these pathologies, proving that they related specifically to copper depletion [ 16 ]. Collectively, these investigations suggested that high iron consumption increases the dietary requirement for copper, supporting the previous assertion that iron supplements should contain extra copper [ 11 ].…”

Copper Deficiency in Liver Diseases: A Case Series and Pathophysiological Considerations

“…To our knowledge, no studies in acute‐on‐chronic liver failure have assessed whether changes in iron homeostasis and neutrophils (whose maturation and function depend on copper) is related to copper deficiency . This may be important, because if copper deficiency indeed exists, it becomes a potential target of intervention in which copper supplementation might (1) improve pathological consequences of iron overload and (2) restore immune cell function as it did in experimental animals …”