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

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...

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Autores principales: Wu, Xiaoyan, Chien, Hsiaotzu, van Wolferen, Monique E., Kruitwagen, Hedwig S., Oosterhoff, Loes A., Penning, Louis C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958483/
https://www.ncbi.nlm.nih.gov/pubmed/31574998
http://dx.doi.org/10.3390/vetsci6040078
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author Wu, Xiaoyan
Chien, Hsiaotzu
van Wolferen, Monique E.
Kruitwagen, Hedwig S.
Oosterhoff, Loes A.
Penning, Louis C.
author_facet Wu, Xiaoyan
Chien, Hsiaotzu
van Wolferen, Monique E.
Kruitwagen, Hedwig S.
Oosterhoff, Loes A.
Penning, Louis C.
author_sort Wu, Xiaoyan
collection PubMed
description 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.
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spelling pubmed-69584832020-01-23 Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs Wu, Xiaoyan Chien, Hsiaotzu van Wolferen, Monique E. Kruitwagen, Hedwig S. Oosterhoff, Loes A. Penning, Louis C. Vet Sci Article 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. MDPI 2019-09-30 /pmc/articles/PMC6958483/ /pubmed/31574998 http://dx.doi.org/10.3390/vetsci6040078 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Xiaoyan
Chien, Hsiaotzu
van Wolferen, Monique E.
Kruitwagen, Hedwig S.
Oosterhoff, Loes A.
Penning, Louis C.
Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title_full Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title_fullStr Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title_full_unstemmed Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title_short Reduced FXR Target Gene Expression in Copper-Laden Livers of COMMD1-Deficient Dogs
title_sort reduced fxr target gene expression in copper-laden livers of commd1-deficient dogs
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958483/
https://www.ncbi.nlm.nih.gov/pubmed/31574998
http://dx.doi.org/10.3390/vetsci6040078
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