Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2023-09-22 , DOI: 10.1016/j.pharmthera.2023.108529 Clavia Ruth Wooton-Kee 1
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.
中文翻译:
核受体功能受损和代谢失调对威尔逊病的治疗意义
铜是许多酶和细胞过程(包括能量稳态和神经递质生物合成)活动所需的必需微量元素;然而,过量的铜积累会导致显着的细胞毒性。肝脏是维持铜稳态的主要器官。铜转运 P 型 ATP 酶 ATP7B 的失活突变会导致威尔逊病,这是一种常染色体隐性遗传疾病,需要终身药物治疗或肝移植。目前的治疗方案仅限于通过螯合螯合铜或减少肠道中的铜吸收(锌疗法)。这些策略的目标是减少游离铜、氧化还原应激和细胞毒性。威尔逊病动物模型和患者的多项证据表明,肝脏代谢发生改变,肝核受体活性受损。核受体是协调正常和患病肝脏中肝脏代谢的转录因子,并且一些肝核受体在威尔逊病和Atp7b −/−模型中活性降低。在这篇综述中,我们总结了威尔逊病病理学基础的基本生理学、威尔逊病动物模型,以及针对威尔逊病患者核受体活性的可能性。