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A conserved role of the insulin-like signaling pathway in diet-dependent uric acid pathologies in Drosophila melanogaster
- Source :
- PLoS Genetics, PLoS genetics, vol 15, iss 8, PLoS Genetics, Vol 15, Iss 8, p e1008318 (2019)
- Publication Year :
- 2018
-
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.<br />Author summary Enzymatic purine degradation in humans ends with uric acid (UA). Multiple genetic and dietary factors raise UA levels above the norm, which is called hyperuricemia or hyperuricosuria when detected in the serum or urine, respectively. Clinical studies report a correlation between elevated UA and a plethora of chronic diseases including crystalopathies like UA kidney stones and gout, or metabolic and vascular disorders such as diabetes, obesity, and coronary artery disease. Here, we identified a regulatory role for the insulin-like signaling cascade affecting UA metabolism using a Drosophila melanogaster model. In the process we determined previously unrecognized potential drug targets to treat elevated UA levels and associated pathologies such as gout or UA kidney stones, with the potential additional benefit of extending human healthspan. Our work also establishes the fly as a model system to characterize the influence of genetic and dietary factors in gout or UA kidney stone development in a manner readily amenable for small-scale screening of drug interventions. The novelty of our findings, their broad impact, and relevance for multiple diseases opens up an important area of research to define mechanisms of UA accumulation.
- Subjects :
- Male
Cancer Research
Candidate gene
Aging
Gout
Urate Oxidase
QH426-470
Biochemistry
Animals, Genetically Modified
Cohort Studies
chemistry.chemical_compound
0302 clinical medicine
Drug Metabolism
Medicine and Health Sciences
2.1 Biological and endogenous factors
Insulin
Aetiology
Genetics (clinical)
0303 health sciences
Gene knockdown
NADPH oxidase
biology
Organic Compounds
Drosophila Melanogaster
Urate oxidase
Eukaryota
Drugs
Single Nucleotide
Animal Models
Middle Aged
3. Good health
Insects
Chemistry
Drosophila melanogaster
Experimental Organism Systems
Gene Knockdown Techniques
Physical Sciences
FOXO3
Purine Metabolism
Female
Drosophila
Signal transduction
Metabolic Networks and Pathways
Signal Transduction
Research Article
medicine.medical_specialty
Arthropoda
Inflammatory Diseases
Longevity
Genetically Modified
Research and Analysis Methods
Polymorphism, Single Nucleotide
03 medical and health sciences
Kidney Calculi
Model Organisms
Rheumatology
Internal medicine
medicine
Genetics
Animals
Humans
Pharmacokinetics
Polymorphism
Molecular Biology
Ecology, Evolution, Behavior and Systematics
030304 developmental biology
Nutrition
Pharmacology
Animal
Organic Chemistry
Chemical Compounds
Organisms
Fungi
NADPH Oxidases
Biology and Life Sciences
Feeding Behavior
biology.organism_classification
Invertebrates
Yeast
Uric Acid
Diet
Disease Models, Animal
Endocrinology
Metabolism
Methotrexate
chemistry
Purines
Disease Models
biology.protein
Animal Studies
Uric acid
030217 neurology & neurosurgery
Developmental Biology
Subjects
Details
- ISSN :
- 15537404
- Volume :
- 15
- Issue :
- 8
- Database :
- OpenAIRE
- Journal :
- PLoS genetics
- Accession number :
- edsair.doi.dedup.....cd3bac64055fca6ec8a3290f3d0437a9