Body distribution of stable copper isotopes during the progression of cholestatic liver disease induced by common bile duct ligation in mice

• Published in: Metallomics Vol. 11; no. 6; pp. 193 - 113
• Main Authors: Costas-Rodríguez, Marta, Van Campenhout, Sanne, Hastuti, Agustina A. M. B, Devisscher, Lindsey, Van Vlierberghe, Hans, Vanhaecke, Frank
• Format: Journal Article
• Language: English
• Published: England Royal Society of Chemistry 19-06-2019
• Subjects: Animal models; Bile; Bile ducts; Bilirubin; Bone composition; Chemokines; Cholestasis; Composition; Copper; Copper isotopes; Cytochrome; Cytochrome b; Cytochromes; Diet; Disease control; Divalent metal transporter-1; Enrichment; Excretion; Fibrosis; Fractionation; Gene expression; Inflammation; Intestine; Isotope fractionation; Isotopes; Liver; Liver diseases; Mice; mRNA; Organs; Protein expression; Proteins; Reductases; Surgery
• ISSN: 1756-5901; 1756-591X
• DOI: 10.1039/c8mt00362a

Patients with chronic liver disease from different aetiologies show a light serum Cu isotopic composition compared to the reference population, with the enrichment in the
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Cu isotope correlating with the severity of the disease. However, the mechanisms underlying Cu isotope fractionation at the onset and during progression of the disease are still unclear. In this work, a common bile duct ligation (CBDL) murine model was used to investigate the effect of cholestasis-induced liver disease on the Cu isotopic composition. Wild type male and female mice underwent surgical ligation of the common bile duct and were sacrificed 2, 4 and 6 weeks, and 4, 6 and 8 weeks after the surgical intervention, respectively. The age- and gender-matched control mice underwent sham surgery. Disease progression was evaluated using serum bilirubin levels, hepatic pro-inflammatory chemokine levels and Metavir fibrosis score. CBDL-operated mice show an overall body enrichment in the light isotope
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Cu. The Cu isotopic composition of organs, bone and serum becomes gradually lighter compared to the sham-operated mice with increasing severity of the disease. The light Cu isotopic composition of the CBDL-operated mice might result from an altered Cu intake and/or excretion. As the intestinal uptake of dietary Cu is largely mediated by transporters of Cu(
i
), mRNA and protein expression levels of two major metal transporters (CTR1 and DMT1) and Cu reductases (STEAP proteins and duodenal cytochrome B) were examined in the duodenal tissues as potential factors inducing Cu isotope fractionation. However, no significant differences in protein expression levels were observed between the CBDL- and sham-operated mice.
The effect of cholestatic liver disease on the body Cu isotopic distribution was investigated in a common bile duct ligation mouse model. The isotopic composition of Cu in serum and organs becomes gradually lighter with increasing severity of the disease.