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 63Cu
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 63Cu. 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.