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The Features of Copper Metabolism in the Rat Liver during Development.

Zatulovskaia YA, Ilyechova EY, Puchkova LV - PLoS ONE (2015)

Bottom Line: 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.The copper routes in newborns are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics, Institute of Physics, Nanotechnology, and Telecommunications, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia.

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.

No MeSH data available.


Related in: MedlinePlus

Schema illustrating copper turnover in the hepatocytes newborns (A) and adults rats (B).(A) In newborns, milk Cp enters to gastrointestinal tract and due to transcytosis transfers into bloodstream, and then it binds with hepatic Cp receptor and proceeds into endolysosomes (EL). At pH > 5, Cu(II) ions are dissociated from milk Cp molecule, Cu(II) is reduced to Cu(I) by STEAP4 and imported by CTR2 in cytosol. Here, Cu(I) is redistributed between Cu(I)-chaperons to be delivered to the places of apo-cuproenzymes formation (trans Golgi network (TGN), cytosol, mitochondria (M)). Also copper is bound with MT, and involved to redox cycle MT/glutathione or delivered to nucleus (Nu) and M as well as exported to extracellular space. As MT is found in mitochondria and nucleus [40], possibly, it transferred copper to the nucleus and mitochondria (or brings copper to their cytosolic surface). (B) In adults, absorbed nutrient copper is imported by CTR1 and distributed between Nu, M, cytosol, and MT [5]. Copper of disturbed cuproenzymes can be re-cyclized via endocytosis or autophagy. In both cases, the copper return in metabolic cycle through STEAP4/CTR2 endolysosomal system.
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pone.0140797.g004: Schema illustrating copper turnover in the hepatocytes newborns (A) and adults rats (B).(A) In newborns, milk Cp enters to gastrointestinal tract and due to transcytosis transfers into bloodstream, and then it binds with hepatic Cp receptor and proceeds into endolysosomes (EL). At pH > 5, Cu(II) ions are dissociated from milk Cp molecule, Cu(II) is reduced to Cu(I) by STEAP4 and imported by CTR2 in cytosol. Here, Cu(I) is redistributed between Cu(I)-chaperons to be delivered to the places of apo-cuproenzymes formation (trans Golgi network (TGN), cytosol, mitochondria (M)). Also copper is bound with MT, and involved to redox cycle MT/glutathione or delivered to nucleus (Nu) and M as well as exported to extracellular space. As MT is found in mitochondria and nucleus [40], possibly, it transferred copper to the nucleus and mitochondria (or brings copper to their cytosolic surface). (B) In adults, absorbed nutrient copper is imported by CTR1 and distributed between Nu, M, cytosol, and MT [5]. Copper of disturbed cuproenzymes can be re-cyclized via endocytosis or autophagy. In both cases, the copper return in metabolic cycle through STEAP4/CTR2 endolysosomal system.

Mentions: In newborns, the main source of nutrient copper is milk Cp, which is synthesized in mammary glands and secreted into milk [27, 79–81]. Milk Cp contains the major fraction of the milk copper [27], and it is transferred from the gastrointestinal tract to the bloodstream by transcytosis [27, 82]. Then the liver cells uptake milk Cp via endocytosis using a specific Cp receptor that is expressed in the hepatocytes of newborns, but not in adults [82, 83]. Accordingly, milk Cp is imported into the endosomes/lysosomes compartment. In lysosomes, at low pH, copper dissociates from the Cp and is reduced to Cu(I) by the Fe/Cu-reductase STEAP4 [84]. After Cu(I) is bound by the copper-binding motifs of CTR2, which takes part in the lysosomal copper turnover [85], and transfers copper to cytosol. There copper is distributed according to the cellular requirements. A model of the putative pathway involving CTR2 in the copper turnover is presented in Fig 4A. It explains the disproportion in Ctr1 and Ctr2 genes activities in the liver of newborns (Fig 3A). In the adult liver, CTR2 continues to take part in the copper re-cyclization from the asialic Cp, which is taken up from the bloodstream through asialoglycoprotein receptors [86]. However, the main copper import pathway in adult rats is going through CTR1; at this time the expression level of the Ctr1 gene increases strongly (Fig 4B).


The Features of Copper Metabolism in the Rat Liver during Development.

Zatulovskaia YA, Ilyechova EY, Puchkova LV - PLoS ONE (2015)

Schema illustrating copper turnover in the hepatocytes newborns (A) and adults rats (B).(A) In newborns, milk Cp enters to gastrointestinal tract and due to transcytosis transfers into bloodstream, and then it binds with hepatic Cp receptor and proceeds into endolysosomes (EL). At pH > 5, Cu(II) ions are dissociated from milk Cp molecule, Cu(II) is reduced to Cu(I) by STEAP4 and imported by CTR2 in cytosol. Here, Cu(I) is redistributed between Cu(I)-chaperons to be delivered to the places of apo-cuproenzymes formation (trans Golgi network (TGN), cytosol, mitochondria (M)). Also copper is bound with MT, and involved to redox cycle MT/glutathione or delivered to nucleus (Nu) and M as well as exported to extracellular space. As MT is found in mitochondria and nucleus [40], possibly, it transferred copper to the nucleus and mitochondria (or brings copper to their cytosolic surface). (B) In adults, absorbed nutrient copper is imported by CTR1 and distributed between Nu, M, cytosol, and MT [5]. Copper of disturbed cuproenzymes can be re-cyclized via endocytosis or autophagy. In both cases, the copper return in metabolic cycle through STEAP4/CTR2 endolysosomal system.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4608700&req=5

pone.0140797.g004: Schema illustrating copper turnover in the hepatocytes newborns (A) and adults rats (B).(A) In newborns, milk Cp enters to gastrointestinal tract and due to transcytosis transfers into bloodstream, and then it binds with hepatic Cp receptor and proceeds into endolysosomes (EL). At pH > 5, Cu(II) ions are dissociated from milk Cp molecule, Cu(II) is reduced to Cu(I) by STEAP4 and imported by CTR2 in cytosol. Here, Cu(I) is redistributed between Cu(I)-chaperons to be delivered to the places of apo-cuproenzymes formation (trans Golgi network (TGN), cytosol, mitochondria (M)). Also copper is bound with MT, and involved to redox cycle MT/glutathione or delivered to nucleus (Nu) and M as well as exported to extracellular space. As MT is found in mitochondria and nucleus [40], possibly, it transferred copper to the nucleus and mitochondria (or brings copper to their cytosolic surface). (B) In adults, absorbed nutrient copper is imported by CTR1 and distributed between Nu, M, cytosol, and MT [5]. Copper of disturbed cuproenzymes can be re-cyclized via endocytosis or autophagy. In both cases, the copper return in metabolic cycle through STEAP4/CTR2 endolysosomal system.
Mentions: In newborns, the main source of nutrient copper is milk Cp, which is synthesized in mammary glands and secreted into milk [27, 79–81]. Milk Cp contains the major fraction of the milk copper [27], and it is transferred from the gastrointestinal tract to the bloodstream by transcytosis [27, 82]. Then the liver cells uptake milk Cp via endocytosis using a specific Cp receptor that is expressed in the hepatocytes of newborns, but not in adults [82, 83]. Accordingly, milk Cp is imported into the endosomes/lysosomes compartment. In lysosomes, at low pH, copper dissociates from the Cp and is reduced to Cu(I) by the Fe/Cu-reductase STEAP4 [84]. After Cu(I) is bound by the copper-binding motifs of CTR2, which takes part in the lysosomal copper turnover [85], and transfers copper to cytosol. There copper is distributed according to the cellular requirements. A model of the putative pathway involving CTR2 in the copper turnover is presented in Fig 4A. It explains the disproportion in Ctr1 and Ctr2 genes activities in the liver of newborns (Fig 3A). In the adult liver, CTR2 continues to take part in the copper re-cyclization from the asialic Cp, which is taken up from the bloodstream through asialoglycoprotein receptors [86]. However, the main copper import pathway in adult rats is going through CTR1; at this time the expression level of the Ctr1 gene increases strongly (Fig 4B).

Bottom Line: 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.The copper routes in newborns are discussed.

View Article: PubMed Central - PubMed

Affiliation: Department of Biophysics, Institute of Physics, Nanotechnology, and Telecommunications, Peter the Great St. Petersburg Polytechnic University, St. Petersburg, Russia.

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.

No MeSH data available.


Related in: MedlinePlus