Oxysterol misbalance critically contributes to Wilson disease pathogenesis

Wilson disease (WD) is a metabolic disorder caused by inactivation of the copper-transporting ATPase 2 (ATP7B) and copper (Cu) overload in tissues. Excess Cu causes oxidative stress and pathologic changes with poorly understood mechanistic connections. In Atp7b(-/-) mice with established liver disease, Cu overload activates the stress-sensitive transcription factor Nrf2 (nuclear factor erythroid-derived 2-like 2). Nrf2 targets, especially sulfotransferase 1e1 (Sult1e1), are strongly induced and cause elevation of sulfated sterols, whereas oxysterols are decreased. This sterol misbalance results in inhibition of the liver X receptor (LXR) and up -regulation of LXR targets associated with inflammatory responses. Pharmacological inhibition of Sult1e1 par-tially reverses oxysterol misbalance and LXR inhibition. Contribution of this pathway to advanced hepatic WD was demonstrated by treating mice with an LXR agonist. Treatment decreased inflammation by reducing expression of proinflammatory molecules, diminished fibrosis by down-regulating the noncanonical trans-forming growth factor-0 signaling pathway, and improved liver morphology and function. Thus, the identi-fied pathway is an important driver of WD.

Automated summary

This study identified an important regulatory pathway in Wilson disease with copper metabolism abnormalities, which can improve liver damage and restore function.