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.
Highlights
Wilson disease (WD) is caused by inactivation of the copper transporter Atp7b and copper overload in tissues
Original Atp7b−/− mice were generated on a hybrid C57BL/6 × 129S6/SvEv background (Atp7b-/–hybrid), whereas Atp7b∆Hep mice were produced on C57BL6 background (Atp7b∆Hep-B6)
We show that the overall pattern of pathological changes in animals with global inactivation of Atp7b is similar at the molecular and cellular levels in strains with different genetic background
Summary
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 Their phenotypes vary, and neither the common response to copper overload nor factors contributing to variability are well defined. The genetically engineered mice with global (in all tissues) inactivation of Atp7b (Atp7b-/– mice) recapitulate many classic features of human WD17 These mice rapidly accumulate Cu in the liver, have impaired Cu incorporation into ceruloplasmin, and show clear signs of liver inflammation and d ysfunction[12,18]. Mice with Atp7b deleted only in hepatocytes (Atp7bΔHep) accumulate Cu in the liver, lack active ceruloplasmin, but do not show hepatocyte ballooning or inflammatory response Instead, these animals have mild obesity and develop liver steatosis at old age[21]. Comparison of liver morphology, function, and proteomes identified the pathways and molecules that were affected in all Atp7b-deficient animals and highlighted a significant impact of systemic Atp7b inactivation on liver morphology and function
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