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

by 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 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 le vels resulted from the loss of the of the urate oxidase (Uro) gene around 15 million years ago. Therefore, we established aDrosophila melanogaster model with reduced expression of the orthologousUro gene to study the pathogenesis arising from elevated UA. ReducedUro expression inDrosophila 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 theDrosophila 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...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research