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Therapeutic implications of impaired nuclear receptor function and dysregulated metabolism in Wilson's disease
Pharmacology & Therapeutics ( IF 12.0 ) Pub Date : 2023-09-22 , DOI: 10.1016/j.pharmthera.2023.108529
Clavia Ruth Wooton-Kee 1
Affiliation  

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:


Wilson 病核受体功能受损和代谢失调的治疗意义



铜是许多酶和细胞过程活性所必需的微量元素,包括能量稳态和神经递质生物合成;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隔离铜或减少肠道对铜的吸收(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。Wilson 病动物模型和患者的几条证据线揭示了肝脏代谢改变和肝核受体活性受损。核受体是协调正常肝脏和患病肝脏代谢的转录因子,在 Wilson 病和 Atp7b−/− 模型中,几种肝核受体的活性降低。在这篇综述中,我们总结了 Wilson 病病理学基础的基本生理学、Wilson 病动物模型以及靶向 Wilson 病患者核受体活性的可能性。

更新日期:2023-09-22
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