Systemic Deletion of Atp7b Modifies the Hepatocytes’ Response to Copper Overload in the Mouse Models of Wilson Disease

Abstract

Wilson disease (WD) is a genetic disorder caused by inactivation of the copper (Cu) transporter Atp7b and Cu overload, especially in the liver. Mice with Atp7b deleted either globally (systemic inactivation) or only in hepatocyte recapitulate various aspects of human WD. However, their phenotypes vary, and neither the common response to Cu overload nor factors responsible for phenotypes variability are well defined. Using metabolic, histologic, and proteome analyses in three mouse strains with mutated Atp7b, we show that global inactivation of Atp7b enhances and specifically modifies the hepatocyte response. 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 the background strain, the metabolism of lipid, nucleic acid, and amino acid 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 reflects the extent of liver injury. The magnitude of proteome changes in different Atp7b-/- strains and in individual animals inversely correlates with their metallothioneins levels rather than Cu content. These results augment the current model of WD pathogenesis, facilitate the identification of WD-specific markers, and assist the development of new therapies