Dev Som, Muchenditsi Abigael, Gottlieb Aline, Deme Pragney, Murphy Sean, Gabrielson Kathleen L, Dong Yixuan, Hughes Robert, Haughey Norman J, Hamilton James P, Lutsenko Svetlana
Department of Physiology, Johns Hopkins University, School of Medicine, 725 North Wolfe St, Baltimore, MD 21205, USA.
Department of Neurology, Johns Hopkins University, School of Medicine, 600 North Wolfe St, Baltimore, MD 21287, USA.
Sci Adv. 2022 Oct 21;8(42):eadc9022. doi: 10.1126/sciadv.adc9022. Epub 2022 Oct 19.
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 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 partially 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 transforming growth factor-β signaling pathway, and improved liver morphology and function. Thus, the identified pathway is an important driver of WD.
威尔逊病（WD）是一种由铜转运ATP酶2（ATP7B）失活和组织中铜（Cu）过载引起的代谢紊乱疾病。过量的铜会导致氧化应激和病理变化，但其机制联系尚不清楚。在已患肝病的小鼠中，铜过载会激活应激敏感转录因子Nrf2（核因子红细胞衍生2样2）。Nrf2的靶标，尤其是磺基转移酶1e1（Sult1e1），会被强烈诱导并导致硫酸化固醇升高，而氧固醇则会减少。这种固醇失衡会导致肝脏X受体（LXR）受到抑制，并上调与炎症反应相关的LXR靶标。对Sult1e1的药理学抑制可部分逆转氧固醇失衡和LXR抑制。通过用LXR激动剂治疗小鼠，证明了该途径对晚期肝性WD的作用。治疗通过降低促炎分子的表达减轻炎症，通过下调非经典转化生长因子-β信号通路减少纤维化，并改善肝脏形态和功能。因此，所确定的途径是WD的一个重要驱动因素。
