The Buck Institute for Research on Aging, Novato, California, United States of America.
Davis School of Gerontology, University of Southern California, Los Angeles, California, United States of America.
PLoS Genet. 2019 Aug 15;15(8):e1008318. doi: 10.1371/journal.pgen.1008318. eCollection 2019 Aug.
Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these disorders, the genetic pathways influencing UA metabolism and the association with disease remain poorly understood. In humans, elevated UA levels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established a Drosophila melanogaster model with reduced expression of the orthologous Uro gene to study the pathogenesis arising from elevated UA. Reduced Uro expression in Drosophila resulted in elevated UA levels, accumulation of concretions in the excretory system, and shortening of lifespan when reared on diets containing high levels of yeast extract. Furthermore, high levels of dietary purines, but not protein or sugar, were sufficient to produce the same effects of shortened lifespan and concretion formation in the Drosophila model. The insulin-like signaling (ILS) pathway has been shown to respond to changes in nutrient status in several species. We observed that genetic suppression of ILS genes reduced both UA levels and concretion load in flies fed high levels of yeast extract. Further support for the role of the ILS pathway in modulating UA metabolism stems from a human candidate gene study identifying SNPs in the ILS genes AKT2 and FOXO3 being associated with serum UA levels or gout. Additionally, inhibition of the NADPH oxidase (NOX) gene rescued the reduced lifespan and concretion phenotypes in Uro knockdown flies. Thus, components of the ILS pathway and the downstream protein NOX represent potential therapeutic targets for treating UA associated pathologies, including gout and kidney stones, as well as extending human healthspan.
尿酸(UA)升高是许多疾病的关键风险因素,包括代谢综合征、痛风和肾结石。尽管这些疾病经常发生,但影响 UA 代谢的遗传途径以及与疾病的关联仍知之甚少。在人类中,UA 水平升高是由于大约 1500 万年前尿酸氧化酶(Uro)基因的丧失引起的。因此,我们建立了一个果蝇模型,该模型中同源 Uro 基因的表达降低,以研究由 UA 升高引起的发病机制。果蝇中 Uro 表达的降低导致 UA 水平升高、排泄系统中结石的积累以及在含有高浓度酵母提取物的饮食中饲养时寿命缩短。此外,高浓度的膳食嘌呤而不是蛋白质或糖足以在果蝇模型中产生同样缩短寿命和结石形成的效果。胰岛素样信号(ILS)途径已被证明可以响应几种物种中营养状况的变化。我们观察到,ILS 基因的遗传抑制降低了喂食高浓度酵母提取物的果蝇中的 UA 水平和结石负荷。ILS 途径在调节 UA 代谢中的作用的进一步支持来自人类候选基因研究,该研究确定了 ILS 基因 AKT2 和 FOXO3 中的 SNPs 与血清 UA 水平或痛风相关。此外,抑制 NADPH 氧化酶(NOX)基因挽救了 Uro 敲低果蝇中寿命缩短和结石表型。因此,ILS 途径的组成部分和下游蛋白 NOX 代表了治疗与 UA 相关的病理的潜在治疗靶点,包括痛风和肾结石,以及延长人类的健康寿命。