Reply

Abstract

Potential conflict of interest: Nothing to report. Reply: We would like to thank you for your interest in our article. We agree that our article, and the work of others,1 has shed a new light on the role of nuclear receptor signaling, and especially liver X receptor/retinoid X receptor (LXR/RXR) activation as a relatively early response to copper misbalance. We propose that drug‐mediated improvement of liver disease in the Wilson disease (WD) mice involves activation of LXR/RXR function not only in hepatocytes, but also in nonparenchymal liver cells (NPCs). Our findings suggest that copper overload negatively regulates LXR and RXR. The mechanisms underlying this regulation by copper remain to be fully elucidated. However, the implication that NPCs are involved in the pathogenesis of WD is an exciting new finding. Investigation of the cross‐talk between hepatocytes and stellate cells/Kupffer cells in this animal model may have ramifications for all fibrotic liver diseases. Although T0901317 was first reported to be a specific LXR agonist,4 we agree that the drug may target other nuclear receptors that form heterodimers with RXR. In fact, it could be that the pleotropic effect of the drug accounts for beneficial anti‐inflammatory and antifibrotic effects that we observe in WD mice. Identifying all targets of T0901317 in the WD model is an important future goal. Future modifications of the drug and/or careful evaluation of dosage/time of treatment are also likely to be necessary to offset the potential untoward effects (such as hepatic steatosis). Nonetheless, modulation of LXR activity appears to have promise as a novel therapy for WD.