Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

Abstract Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the...

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Autores principales:	Abigael Muchenditsi, C. Conover Talbot, Aline Gottlieb, Haojun Yang, Byunghak Kang, Tatiana Boronina, Robert Cole, Li Wang, Som Dev, James P. Hamilton, Svetlana Lutsenko
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/087df558e0b04edcbd0b256f2e46f641
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spelling	oai:doaj.org-article:087df558e0b04edcbd0b256f2e46f6412021-12-02T15:54:02ZSystemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease10.1038/s41598-021-84894-32045-2322https://doaj.org/article/087df558e0b04edcbd0b256f2e46f6412021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84894-3https://doaj.org/toc/2045-2322Abstract Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b −/− animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.Abigael MuchenditsiC. Conover TalbotAline GottliebHaojun YangByunghak KangTatiana BoroninaRobert ColeLi WangSom DevJames P. HamiltonSvetlana LutsenkoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Abigael Muchenditsi C. Conover Talbot Aline Gottlieb Haojun Yang Byunghak Kang Tatiana Boronina Robert Cole Li Wang Som Dev James P. Hamilton Svetlana Lutsenko Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
description	Abstract Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human disease. However, their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. Using metabolic, histologic, and proteome analyses in three Atp7b-deficient mouse strains, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response to Cu overload. The loss of Atp7b only in hepatocytes dysregulates lipid and nucleic acid metabolisms and increases the abundance of respiratory chain components and redox balancing enzymes. In global knockouts, independently of their background, the metabolism of lipid, nucleic acid, and amino acids is inhibited, respiratory chain components are down-regulated, inflammatory response and regulation of chromosomal replication are enhanced. Decrease in glucokinase and lathosterol oxidase and elevation of mucin-13 and S100A10 are observed in all Atp7b mutant strains and reflect the extent of liver injury. The magnitude of proteomic changes in Atp7b −/− animals inversely correlates with the metallothioneins levels rather than liver Cu content. These findings facilitate identification of WD-specific metabolic and proteomic changes for diagnostic and treatment.
format	article
author	Abigael Muchenditsi C. Conover Talbot Aline Gottlieb Haojun Yang Byunghak Kang Tatiana Boronina Robert Cole Li Wang Som Dev James P. Hamilton Svetlana Lutsenko
author_facet	Abigael Muchenditsi C. Conover Talbot Aline Gottlieb Haojun Yang Byunghak Kang Tatiana Boronina Robert Cole Li Wang Som Dev James P. Hamilton Svetlana Lutsenko
author_sort	Abigael Muchenditsi
title	Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
title_short	Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
title_full	Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
title_fullStr	Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
title_full_unstemmed	Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease
title_sort	systemic deletion of atp7b modifies the hepatocytes’ response to copper overload in the mouse models of wilson disease
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/087df558e0b04edcbd0b256f2e46f641
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Systemic deletion of Atp7b modifies the hepatocytes’ response to copper overload in the mouse models of Wilson disease

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