A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster.
Animals
Animals, Genetically Modified
Cohort Studies
Disease Models, Animal
Drosophila melanogaster
Feeding Behavior
Female
Gene Knockdown Techniques
Gout
/ etiology
Humans
Insulin
/ metabolism
Kidney Calculi
/ etiology
Longevity
/ genetics
Male
Metabolic Networks and Pathways
/ genetics
Middle Aged
NADPH Oxidases
/ genetics
Polymorphism, Single Nucleotide
Purines
/ administration & dosage
Signal Transduction
/ genetics
Urate Oxidase
/ genetics
Uric Acid
/ metabolism
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
08
11
2018
accepted:
17
07
2019
entrez:
16
8
2019
pubmed:
16
8
2019
medline:
8
1
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31415568
doi: 10.1371/journal.pgen.1008318
pii: PGENETICS-D-18-02130
pmc: PMC6695094
doi:
Substances chimiques
Insulin
0
Purines
0
Uric Acid
268B43MJ25
NADPH Oxidases
EC 1.6.3.-
Nox protein, Drosophila
EC 1.6.3.1
Urate Oxidase
EC 1.7.3.3
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1008318Subventions
Organisme : NIA NIH HHS
ID : F31 AG062112
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG045835
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103729
Pays : United States
Organisme : NIA NIH HHS
ID : R01 AG038688
Pays : United States
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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