Abstract
We have previously shown that (1) an acute deficiency in blood serum holo-ceruloplasmin (Cp) developed in rats that were fed fodder containing silver ions (Ag-fodder) for one month and (2) the deficiency in holo-Cp was compensated by non-hepatic holo-Cp synthesis in rats that were chronically fed Ag-fodder for 6 months (Ag-rats). The purpose of the present study is to identify the organ(s) that compensate for the hepatic holo-Cp deficiency in the circulation. This study was performed on rats that were fed Ag-fodder (40 mg Ag·kg-1 body mass daily) for 6 months. The relative expression levels of the genes responsible for copper status were measured by RT-PCR. The in vitro synthesis and secretion of [14C]Cp were analyzed using a metabolic labeling approach. Oxidase activity was determined using a gel assay with o-dianisidine. Copper status and some hematological indexes were measured. Differential centrifugation, immunoblotting, immunoelectrophoresis, and atomic absorption spectrometry were included in the investigation. In the Ag-rats, silver accumulation was tissue-specific. Skeletal muscles and internal (IAT) and subcutaneous (SAT) adipose tissues did not accumulate silver significantly. In SAT, the mRNAs for the soluble and glycosylphosphatidylinositol-anchored ceruloplasmin isoforms were expressed, and their relative levels were increased two-fold in the Ag-rats. In parallel, the levels of the genes responsible for Cp metallation (Ctr1 and Atp7a/b) increased correspondingly. In the SAT of the Ag-rats, Cp oxidase activity was observed in the Golgi complex and plasma membrane. Moreover, full-length [14C]Cp polypeptides were released into the medium by slices of SAT. The possibilities that SAT is part of a system that controls the copper balance in mammals, and it plays a significant role in supporting copper homeostasis throughout the body are discussed.
Highlights
The biological role of copper as a catalytic and structural cofactor of vitally important enzymes and as a potentially toxic agent was established more than half a century ago [1,2]
An organ that could compensate for the deficiency in hepatic holo-Cp in the Ag-rats should meet at least the following two criteria: (1) it does not accumulate silver effectively so silver is not included in holo-Cp (Fig 1A), and (2) it expresses the Cp gene
The organs were arranged by decreasing silver storage capacity: liver, spleen, testis, kidney, lung, brain, heart and others, which accumulate silver at the background level (skeletal muscles, internal adipose tissue (IAT) and subcutaneous adipose tissue (SAT))
Summary
The biological role of copper as a catalytic and structural cofactor of vitally important enzymes and as a potentially toxic agent was established more than half a century ago [1,2]. 20 years, the system of safe copper transport from extracellular spaces to the places where cuproenzymes are formed was discovered and studied in detail [3]. In the last 5 years, it has become evident that copper participates in the regulation of proliferation, apoptosis, neovascularization, neurotransmission, and signaling; it may be viewed as a secondary messenger, somewhat similar to calcium [4,5,6,7,8]. Disturbances in copper homeostasis lead to the development of cardiovascular, neurodegenerative, and oncological diseases [2,7,9]. The attention of researchers has mainly been focused on intracellular copper homeodynamics. Homeostasis and the maintenance of copper balance in body fluids are insufficiently studied
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