Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease

Copper is an essential trace element that is required for the activity of many enzymes and cellular processes, including energy homeostasis and neurotransmitter biosynthesis; however, excess copper accumulation results in significant cellular toxicity. The liver is the major organ for maintaining copper homeostasis. Inactivating mutations of the copper-transporting P-type ATPase, ATP7B, result in Wilson's disease, an autosomal recessive disorder that requires life-long medicinal therapy or liver transplantation. Current treatment protocols are limited to either sequestration of copper via chelation or reduction of copper absorption in the gut (zinc therapy). The goal of these strategies is to reduce free copper, redox stress, and cellular toxicity. Several lines of evidence in Wilson's disease animal models and patients have revealed altered hepatic metabolism and impaired hepatic nuclear receptor activity. Nuclear receptors are transcription factors that coordinate hepatic metabolism in normal and diseased livers, and several hepatic nuclear receptors have decreased activity in Wilson's disease and Atp7b−/− models. In this review, we summarize the basic physiology that underlies Wilson's disease pathology, Wilson's disease animal models, and the possibility of targeting nuclear receptor activity in Wilson's disease patients.