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Open AccessArticle

Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs

Department Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, P.O. BOX 80.154, NL-3508 TD Utrecht, the Netherlands
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Vet. Sci. 2019, 6(4), 78;
Received: 28 August 2019 / Revised: 24 September 2019 / Accepted: 25 September 2019 / Published: 30 September 2019
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. View Full-Text
Keywords: copper toxicosis; Bedlington terrier; nuclear receptor; COMMD1 copper toxicosis; Bedlington terrier; nuclear receptor; COMMD1
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Wu, X.; Chien, H.; van Wolferen, M.E.; Kruitwagen, H.S.; Oosterhoff, L.A.; Penning, L.C. Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs. Vet. Sci. 2019, 6, 78.

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