Activation of liver X receptor/retinoid X receptor pathway ameliorates liver disease in Atp7B−/− (Wilson disease) mice

Abstract

Wilson disease (WD) is a hepatoneurologic disorder caused by mutations in the copper-transporter ATP7B. Copper accumulation in the liver is a hallmark of WD. Current therapy is based on copper chelation, which decreases the manifestations of liver disease, but often worsens neurologic symptoms. We demonstrate that in Atp7b−/− mice, an animal model of WD, liver function can be significantly improved without copper chelation. Analysis of transcriptional and metabolic changes in samples from WD patients and Atp7b−/− mice identified disregulation of nuclear receptors (NR), especially the LXR/RXR heterodimer, as an important event in WD pathogenesis. Treating Atp7b−/− mice with the LXR agonist T0901317 ameliorated disease manifestations despite significant copper overload. Genetic markers of liver fibrosis and inflammatory cytokines were significantly decreased, lipid profiles normalized and liver function and histology was improved. In conclusion, the results demonstrate the major role of an altered nuclear receptor function in the pathogenesis of WD; and suggest that modulation of nuclear receptor activity should be explored as a supplementary approach to improving liver function in WD.

Animal models of Wilson disease

“…; Hamilton et al . ). At this stage, genes involved cell cycle machinery and DNA repair are prominently up‐regulated (Ralle et al .…”

“…; Hamilton et al . ). Macroscopic changes in the liver of Atp7b −/− mice can be seen at 7 months, with irregular shapes and regeneration nodes apparent (Buiakova et al .…”

“…), while administration of an liver X receptor agonist can normalise lipid metabolism, decrease liver inflammation and fibrosis and improve liver function in Atp7b −/− mice (Hamilton et al . ).…”

“…These abnormalities are also present in the liver of human WD patients (Hamilton et al . ; Wooton‐Kee et al . ).…”

Reply

“…At this age, the mice have evidence of elevated hepatic copper, but liver disease has not yet developed. (1) We were able to prevent the development of liver disease using the liver X receptor (LXR)/retinoid X receptor agonist, yet we did not affect hepatic copper (which remained high). We have not yet been able to definitively show how copper disrupts LXR-mediated lipid metabolism in animals, but in vitro experiments have shown that copper can alter nuclear receptor signaling.…”