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

• DOI: 10.1371/journal.pgen.1008318
• Publication Date: 2019-08-15T17:29:26Z
• Authors: Sven Lang; Tyler A. Hilsabeck; Kenneth A. Wilson; Amit Sharma; Neelanjan Bose; Deanna J. Brackman; Jennifer N. Beck; Ling Chen; Mark A. Watson; David W. Killilea; Sunita Ho; Arnold Kahn; Kathleen Giacomini; Marshall L. Stoller; Thomas Chi; Pankaj Kapahi
• Keywords: Xanthine dehydrogenase; Urate Oxidase

Elevated uric acid (UA) is a key risk factor for many disorders, including metabolic syndrome, gout and kidney stones. Despite frequent occurrence of these the genetic pathways influencing UA metabolism association with disease remain poorly understood. In humans, elevated levels resulted from loss urate oxidase (Uro) gene around 15 million years ago. Therefore, we established Drosophila melanogaster model reduced expression orthologous Uro to study pathogenesis arising UA. Reduced in levels, accumulation concretions excretory system, shortening lifespan when reared on diets containing high yeast extract. Furthermore, dietary purines, but not protein or sugar, were sufficient produce same effects shortened concretion formation model. The insulin-like signaling (ILS) pathway has been shown respond changes nutrient status several species. We observed that suppression ILS genes both load flies fed Further support role modulating stems human candidate identifying SNPs AKT2 FOXO3 being associated serum gout. Additionally, inhibition NADPH (NOX) rescued phenotypes knockdown flies. Thus, components downstream NOX represent potential therapeutic targets treating pathologies, stones, as well extending healthspan.