Abstract
Wilson’s disease (WD), an autosomal recessive disorder, results in copper accumulation in the liver as a consequence of mutations in the gene ATPase copper transporting beta (ATP7B). The disease is characterized by chronic hepatitis, eventually resulting in liver cirrhosis. Recent studies have shown that dysregulation of nuclear receptors (NR) by high hepatic copper levels is an important event in the pathogenesis of liver disease in WD. Intracellular trafficking of ATP7B is mediated by COMMD1 and, in Bedlington terriers, a mutation in the COMMD1 gene results in high hepatic copper levels. Here, we demonstrate a reduced Farnesoid X nuclear receptor (FXR)-activity in liver biopsies of COMMD1-deficient dogs with copper toxicosis, a unique large animal model of WD. FXR-induced target genes, small heterodimer partner (SHP), and apolipoprotein E (ApoE) were down-regulated in liver samples from COMMD1-deficient dogs with hepatic copper accumulation. In contrast, the relative mRNA levels of the two CYP-enzymes (reduced by FXR activity) was similar in both groups. These data are in line with the previously observed reduced FXR activity in livers of ATP7B−/− mice and WD patients. Therefore, these data further corroborate on the importance of the COMMD1-deficient dogs as a large animal model for WD.
Highlights
Wilson’s Disease (WD) is an inherited disease characterized by excessive hepatic accumulation of the trace element copper, leading to chronic liver disease and cirrhosis [1]
To measure Farnesoid X nuclear receptor (FXR) activity, we analyzed the relative expression of four gene products which are induced by FXR; namely, small heterodimer partner (SHP), Bile Salt Export
As no difference in relative mRNA expression levels of the six measured FXR target genes was observed between COMMD1+/+ and COMMD1+/− liver samples—as expected, based on the normal hepatic copper levels and healthy histology—these two groups were combined and compared to samples from copper-laden livers of COMMD1-deficient dogs
Summary
Wilson’s Disease (WD) is an inherited disease characterized by excessive hepatic accumulation of the trace element copper, leading to chronic liver disease and cirrhosis [1]. This autosomal recessive disorder is caused by mutations in the gene coding for ATPase copper transporting beta (ATP7B) [2]. It seems unlikely that copper-induced Fenton-like reactions are causative in copper overload models [5,6]. Another explanation of copper overload-induced cellular disturbances needs to be investigated
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