The Features of Copper Metabolism in the Rat Liver during Development

Abstract

Strong interest in copper homeostasis is due to the fact that copper is simultaneously a catalytic co-factor of the vital enzymes, a participant in signaling, and a toxic agent provoking oxidative stress. In mammals, during development copper metabolism is conformed to two types. In embryonic type copper metabolism (ETCM), newborns accumulate copper to high level in the liver because its excretion via bile is blocked; and serum copper concentration is low because ceruloplasmin (the main copper-containing protein of plasma) gene expression is repressed. In the late weaning, the ETCM switches to the adult type copper metabolism (ATCM), which is manifested by the unlocking of copper excretion and the induction of ceruloplasmin gene activity. The considerable progress has been made in the understanding of the molecular basis of copper metabolic turnover in the ATCM, but many aspects of the copper homeostasis in the ETCM remain unclear. The aim of this study was to investigate the copper metabolism during transition from the ETCM (up to 12-days-old) to the ATCM in the rats. It was shown that in the liver, copper was accumulated in the nuclei during the first 5 days of life, and then it was re-located to the mitochondria. In parallel with the mitochondria, copper bulk bound with cytosolic metallothionein was increased. All compartments of the liver cells rapidly lost most of their copper on the 13th day of life. In newborns, serum copper concentration was low, and its major fraction was associated with holo-Cp, however, a small portion of copper was bound to extracellular metallothionein and a substance that was slowly eluted during gel-filtration. In adults, serum copper concentration increased by about a factor of 3, while metallothionein-bound copper level decreased by a factor of 2. During development, the expression level of Cp, Sod1, Cox4i1, Atp7b, Ctr1, Ctr2, Cox17, and Ccs genes was significantly increased, and metallothionein was decreased. Atp7a gene’s activity was fully repressed. The copper routes in newborns are discussed.

Low Hepatic Tissue Copper in Pediatric Nonalcoholic Fatty Liver Disease

“…Copper is an essential microelement and is utilized by enzymes controlling a wide range of intracellular processes including oxidative phosphorylation, scavenging of reactive oxygen species, mitochondrial respiration, post-translation processing of collagen, elastin and neuropeptides, synthesis of neurotransmitters as well as those important in bidirectional transfer of iron ions across plasma membranes 2, 3 . The balance of copper in biologic systems is vital because excess free copper ions can cause damage to cellular components; yet deficiency will interrupt the function of cellular enzymes that require this cofactor 3 .…”

Copper Metabolism of Newborns Is Adapted to Milk Ceruloplasmin As a Nutritive Source of Copper

“…is accumulated in the liver [16,[107][108][109]. The concentration of metallothionein-associated copper in blood serum of the newborns is 2 times higher than in adults [108]. The distribution of copper between the liver and blood in ETCM and the pathways of its excretion corresponds to that observed in Wilson's disease [14].…”

“…Ontogenetic development of mammals relies on two systems of cuproenzyme metalation, which successively operate in the liver. is accumulated in the liver [16,[107][108][109]. The concentration of metallothionein-associated copper in blood serum of the newborns is 2 times higher than in adults [108].…”

High sucrose low copper diet in pregnant diabetic rats induces transient oxidative stress, hypoxia, and apoptosis in the offspring's liver

“…During weaning, the liver copper decreased and its serum level increases. Since we switched the maternal diet after parturition, their blood and milk copper increased, and due to the ability of the pups to accumulate copper in their liver the impact of the low copper decreased (Zatulovskaia, Ilyechova, & Puchkova, 2015).…”