RRC ID 57467
Author Lang S, Hilsabeck TA, Wilson KA, Sharma A, Bose N, Brackman DJ, Beck JN, Chen L, Watson MA, Killilea DW, Ho S, Kahn A, Giacomini K, Stoller ML, Chi T, Kapahi P.
Title A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.
Journal PLoS Genet
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.
Volume 15(8)
Pages e1008318
Published 2019-8-1
DOI 10.1371/journal.pgen.1008318
PMID 31415568
PMC PMC6695094
MeSH Animals Animals, Genetically Modified Cohort Studies Disease Models, Animal Drosophila melanogaster Feeding Behavior Female Gene Knockdown Techniques Gout / etiology* Gout / metabolism Humans Insulin / metabolism Kidney Calculi / etiology* Kidney Calculi / metabolism Longevity / genetics Male Metabolic Networks and Pathways / genetics* Middle Aged NADPH Oxidases / genetics NADPH Oxidases / metabolism Polymorphism, Single Nucleotide Purines / administration & dosage Purines / adverse effects Signal Transduction / genetics* Urate Oxidase / genetics Urate Oxidase / metabolism Uric Acid / metabolism*
IF 5.224
Times Cited 3
Drosophila 7171R-1