Metabolic dysregulation in the<i>Atp7b</i>^−/−Wilson’s disease mouse model

Abstract

Inactivating mutations in the copper transporter <i>Atp7b</i> result in Wilson's disease. The <i>Atp7b</i>^-/- mouse develops hallmarks of Wilson's disease. The activity of several nuclear receptors decreased in <i>Atp7b</i>^<i>-/-</i> mice, and nuclear receptors are critical for maintaining metabolic homeostasis. Therefore, we anticipated that <i>Atp7b</i>^<i>-/-</i> mice would exhibit altered progression of diet-induced obesity, fatty liver, and insulin resistance. Following 10 wk on a chow or Western-type diet (40% kcal fat), parameters of glucose and lipid homeostasis were measured. Hepatic metabolites were measured by liquid chromatography-mass spectrometry and correlated with transcriptomic data. <i>Atp7b</i>^-/- mice fed a chow diet presented with blunted body-weight gain over time, had lower fat mass, and were more glucose tolerant than wild type (WT) littermate controls. On the Western diet, <i>Atp7b</i>^<i>-/-</i> mice exhibited reduced body weight, adiposity, and hepatic steatosis compared with WT controls. <i>Atp7b</i>^<i>-/-</i> mice fed either diet were more insulin sensitive than WT controls; however, fasted <i>Atp7b</i>^-/- mice exhibited hypoglycemia after administration of insulin due to an impaired glucose counterregulatory response, as evidenced by reduced hepatic glucose production. Coupling gene expression with metabolomic analyses, we observed striking changes in hepatic metabolic profiles in <i>Atp7b</i>^<i>-/-</i> mice, including increases in glycolytic intermediates and components of the tricarboxylic acid cycle. In addition, the active phosphorylated form of AMP kinase was significantly increased in <i>Atp7b</i>^<i>-/-</i> mice relative to WT controls. Alterations in hepatic metabolic profiles and nuclear receptor signaling were associated with improved glucose tolerance and insulin sensitivity as well as with impaired fasting glucose production in <i>Atp7b</i>^<i>-/-</i> mice.