Copper (Cu) is an essential cofactor for various enzymatic activities including mitochondrial electron transport, iron mobilization, and peptide hormone maturation. Consequently, Cu dysregulation is associated with fatal neonatal disease, liver and cardiac dysfunction, and anemia. While the Cu transporter ATP7A plays a major role in both intestinal Cu mobilization to the periphery and prevention of Cu over-accumulation, it is unclear how regulation of ATP7A contributes to Cu homeostasis in response to systemic Cu fluctuation. Here we show, using Cu-deficient mouse models, that steady-state levels of ATP7A are lower in peripheral tissues (including the heart, spleen, and liver) under Cu deficiency and that subcutaneous administration of Cu to these animals restore normal ATP7A levels in these tissues. Strikingly, ATP7A in the intestine is regulated in the opposite manner - low systemic Cu increases ATP7A while subcutaneous Cu administration decreases ATP7A suggesting that intestine-specific non-autonomous regulation of ATP7A abundance may serve as a key homeostatic control for Cu export into the circulation. Our results support a systemic model for how a single transporter can be inversely regulated in a tissue-specific manner to maintain organismal Cu homeostasis.

Many studies have focused on the influence of dietary cation-anion difference (DCAD) on animal performance but few have examined the effect of DCAD on the rumen ionic environment. The objective of this study was to examine the effects of DCAD, cation source (Na vs. K), and anion source (Cl vs. bicarbonate or carbonate) on rumen environment and fermentation. The study used 5 rumen-fistulated dairy cows and 5 dietary treatments that were applied using a 5×5 Latin square design with 2-wk experimental periods. Treatments consisted of (1) the basal total mixed ration (TMR); (2) the basal TMR plus 340mEq/kg of Na (dry matter basis) using NaCl; (3) the basal TMR plus 340mEq/kg of K using KCl; (4) the basal TMR plus 340mEq/kg of Na using NaHCO3; and (5) the basal TMR plus 340mEq/kg of K using K2CO3. On the last day of each experimental period, rumen samples were collected and pooled from 5 different locations at 0, 1.5, 3, 4.5, 6, 9, and 12h postfeeding for measurement of rumen pH and concentrations of strong ions and volatile fatty acids (VFA). Dietary supplementation of individual strong ions increased the corresponding rumen ion concentration. Rumen Na was decreased by 24mEq/L when K was substituted for Na in the diet, but added dietary Na had no effect on rumen K. Rumen Cl was increased by 10mEq/L in diets supplemented with Cl. Cation source had no effect on rumen pH or total VFA concentration. Increased DCAD increased rumen pH by 0.10 pH units and increased rumen acetate by 4mEq/L but did not increase total VFA. This study demonstrated that rumen ion concentrations can be manipulated by dietary ion concentrations. If production and feed efficiency responses to DCAD and ionophores in the diet are affected by rumen Na and K concentrations, then manipulating dietary Na and K could be used either to enhance or diminish those responses.

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