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

Sven Lang,Ling Chen,Jennifer N Beck,Pankaj Kapahi,Sunita Ho,David W Killilea,Arnold Kahn,Neelanjan Bose,Amit Sharma,Deanna J Brackman,Tyler A Hilsabeck,Marshall L Stoller,Kenneth A Wilson,Thomas Chi,Kathleen Giacomini,Mark A Watson,William Wei-Hua Ja

doi:10.1371/journal.pgen.1008318

Abstract

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.

Highlights

Purine homeostasis represents a conserved metabolic pathway that is sustained by multiple enzymes orchestrating de novo synthesis, salvage, and degradation of purine intermediates
Multiple genetic and dietary factors raise uric acid (UA) levels above the norm, which is called hyperuricemia or hyperuricosuria when detected in the serum or urine, respectively
We identified a regulatory role for the insulin-like signaling cascade affecting UA metabolism using a Drosophila melanogaster model

Summary

Introduction

Purine homeostasis represents a conserved metabolic pathway that is sustained by multiple enzymes orchestrating de novo synthesis, salvage, and degradation of purine intermediates. Due to multiple point mutations in the urate oxidase gene (Uro) human ancestors lost the ability to synthesize a functional urate oxidase, increasing serum and urinary UA levels [1,2,3,4,5]. Several genetic risk factors are associated with increased UA levels including genes of purine homeostasis, glucose metabolism, or UA transporters. Dietary risk factors are sugar-sweetened beverages, alcohol, red meat, and seafood, all found in over-abundance in the Western diet [8, 9]

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Results

Conclusion