Copper Transport and Metabolism Are Normal in Aceruloplasminemic Mice

Abstract

Ceruloplasmin is an abundant serum glycoprotein containing greater than 95% of the copper found in the plasma of vertebrate species. Although this protein is known to function as an essential ferroxidase, the role of ceruloplasmin in copper transport and metabolism remains unclear. To elucidate the role of ceruloplasmin in copper metabolism, the kinetics of copper absorption, transport, distribution, and excretion were examined utilizing (64)Cu in wild-type and aceruloplasminemic mice. No differences in gastrointestinal absorption, hepatic uptake, or biliary excretion were observed in these animals. Furthermore, steady state measurements of tissue copper content utilizing (64)Cu and atomic absorption spectroscopy revealed no differences in the copper content of the brain, heart, spleen, and kidney. Consistent with these findings, the activity of copper-zinc superoxide dismutase in these tissues was equivalent in wild-type and ceruloplasmin-deficient mice. Hepatic iron was elevated 3.5-fold in aceruloplasminemic mice because of the loss of ferroxidase function. Hepatic copper content was markedly increased in aceruloplasminemic mice. As no differences were observed in copper absorption or biliary copper excretion, these data suggest that in these animals, hepatocyte copper intended for ceruloplasmin incorporation is trafficked into a compartment that is less available for biliary copper excretion. Taken together, these data reveal no essential role for ceruloplasmin in copper metabolism and suggest a previously unappreciated complexity to the subcellular distribution of this metal within the hepatocyte secretory pathway.

Re-evaluation of the diagnostic criteria for Wilson disease in children with mild liver disease

“…In aceruloplasminemic mice, the liver copper content is augmented, but normal copper absorption, transport, distribution, and excretion are observed. 30 Furthermore, in our study, we found that patients with NRH of the liver also shared some features with WD patients. NRH is an uncommon benign condition characterized by diffuse transformation of the normal hepatic parenchyma into small, regenerative nodules without fibrosis; we found it to be associated with high copper urine excretion after PCT, but the latter finding is difficult to interpret.…”

Copper binding components of blood plasma and organs, and their responses to influx of large doses of 65Cu, in the mouse

“…This is consistent with our earlier findings (Montaser et al 1992) and is also in accord with the observation that mice also have less copper in their livers and kidneys. Thus, Meyer et al (2001) reported liver concentrations of 2.6 ± 0.2 μg/g for 10-12 week old mice of the same strain used here, which is significantly lower than the values of 4.6 ± 1.1 and 6.2 ± 0.8 reported for rats and humans, respectively (Means ± SD, N=9-23; Linder 1991. Similarly, mouse kidney values of 3.8 ± 0.1 (Meyer et al 2001) are significantly less than the values of 7.9 and 12 for rats and humans, respectively (Linder 1991).…”

“…Thus, Meyer et al (2001) reported liver concentrations of 2.6 ± 0.2 μg/g for 10-12 week old mice of the same strain used here, which is significantly lower than the values of 4.6 ± 1.1 and 6.2 ± 0.8 reported for rats and humans, respectively (Means ± SD, N=9-23; Linder 1991. Similarly, mouse kidney values of 3.8 ± 0.1 (Meyer et al 2001) are significantly less than the values of 7.9 and 12 for rats and humans, respectively (Linder 1991). Heart and brain did not show marked interspecies differences.…”

Copper transporter 1, metallothionein and glutathione reductase genes are differentially expressed in tissues of sea bream (Sparus aurata) after exposure to dietary or waterborne copper

“…To date three candidates for circulatory Cu transport have been suggested. Ceruloplasmin, a protein essential for iron homeostasis, contains up to 95 % of Cu in the blood, but deficiency of the protein has no effect on Cu transport (Meyer et al, 2001). Similarly, deficiency of serum albumin, to which Cu 2+ binds with high affinity, has no Cu-transport or distribution effects (Vargas et al, 1994).…”