A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster

Author summary Enzymatic purine degradation in humans ends with uric acid (UA). Multiple genetic and dietary factors raise UA levels above the norm, which is called hyperuricemia or hyperuricosuria when detected in the serum or urine, respectively. Clinical studies report a correlation between elevated UA and a plethora of chronic diseases including crystalopathies like UA kidney stones and gout, or metabolic and vascular disorders such as diabetes, obesity, and coronary artery disease. Here, we identified a regulatory role for the insulin-like signaling cascade affecting UA metabolism using a Drosophila melanogaster model. In the process we determined previously unrecognized potential drug targets to treat elevated UA levels and associated pathologies such as gout or UA kidney stones, with the potential additional benefit of extending human healthspan. Our work also establishes the fly as a model system to characterize the influence of genetic and dietary factors in gout or UA kidney stone development in a manner readily amenable for small-scale screening of drug interventions. The novelty of our findings, their broad impact, and relevance for multiple diseases opens up an important area of research to define mechanisms of UA accumulation. 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.