Dataset Information

Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional WRN mutant protein

ABSTRACT: Werner syndrome (WS) is a premature aging disorder caused by mutations in a DNA helicase/exonuclease. Mice lacking the helicase domain of the Wrn protein orthologue exhibit transcriptomic and metabolic alterations, some of which are reversed by vitamin C. Recent studies on the liver of these animals indicated that the Wrn mutant protein is associated with the endoplasmic reticulum (ER) resulting in an ER stress response. In this study, we identified liver proteins that exhibit actual level differences in the ER fraction between wild type and Wrn mutant mice using quantitative proteomic profiling with label-free Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Multiple Reaction Monitoring (MRM) and immunoblotting were performed to validate findings in a secondary independent cohort of wild type and Wrn mutant mice in the presence or absence of vitamin C in drinking water. The list of identified proteins showing significant altered expression levels was compared to transcriptomic results that were obtained in previous studies to assess the extent of correlation between the mRNA levels and their corresponding encoded protein levels in the liver of our different mouse cohorts.

INSTRUMENT(S): Orbitrap Fusion ETD

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

DISEASE(S): Werner Syndrome

SUBMITTER: Michel Lebel

LAB HEAD: Michel Lebel

PROVIDER: PXD007758 | Pride | 2018-03-02

REPOSITORIES: Pride

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Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional Werner syndrome (Wrn) mutant protein.

Aumailley Lucie L Roux-Dalvai Florence F Kelly Isabelle I Droit Arnaud A Lebel Michel M

PloS one 20180301 3

Werner syndrome (WS) is a premature aging disorder caused by mutations in a protein containing both a DNA exonuclease and DNA helicase domain. Mice lacking the helicase domain of the Wrn protein orthologue exhibit transcriptomic and metabolic alterations, some of which are reversed by vitamin C. Recent studies on these animals indicated that the mutant protein is associated with enriched endoplasmic reticulum (ER) fractions of tissues resulting in an ER stress response. In this study, we identif ...[more]

PMID: 29494634

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Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 9 months old Wrn mutant and wild type animals. Gene set enrichment analysis of the microarray data indicated that Wrn mutant mice exhibited down-regulation of genes normally decreased in several transgenic mouse models of hepatoma and during caloric restriction. Wrn mutant mice also altered the expression of genes involved in inflammation as well as in glutathione and xenobiotic metabolisms. These results indicate that Wrn mutant mice respond to the observed oxidative stress by altering the necessary pathways to survive. Vitamin C supplementation rescued the life span expectancy of Wrn mutant mice and reversed several age-related abnormalities in adipose, cardiac, and liver tissues, genomic integrity and inflammatory status. Finally, gene set enrichment analyses revealed that vitamin C decreased genes normally up regulated in human WS fibroblasts and cancers and it increased genes involved in tissue injury response and adipocyte dedifferentiation in obese mice. Experiment Overall Design: Microarray analyses were performed on the liver tissues of 9 months old mice. Four independent biological replicates of this experiment (wild type vs Wrn mutant or wild type vs vitamin C treated mutant mice) were carried out with a dye swap on two replicates of each genotype.

Project description:Werner syndrome (WS) is a rare disorder characterized by the premature onset of a number of age-related diseases. The gene responsible for WS is believed to be involved in different aspects of transcription, replication, and/or DNA repair. We generated a mouse model with a deletion in the helicase domain of the murine WRN homologue that recapitulates most of the WS phenotypes including an abnormal hyaluronic acid excretion, higher reactive oxygen species (ROS) levels, increased genomic instability and cancer incidence resulting in a 10-15% decreased life span expectancy. In addition, WS patients and Wrn mutant mice show hallmarks of a metabolic syndrome including premature visceral obesity, hypertriglyceridemia, insulin-resistant diabetes type 2 and associated cardiovascular diseases. In this study, we compared the expression profile of liver tissues from 9 months old Wrn mutant treated with a standard diet supplemented with 0.04% resveratrol and wild type animals fed with standard diet only. Resveratrol is a calorie restriction mimetic. Gene set enrichment analysis of the microarray data indicated that reseveratrol-treated Wrn mutant mice exhibited down-regulation of genes normally decreased in several transgenic mouse models of hepatoma. In addition, resvratrol-treated Wrn mutant mice also exhibited a decrease in the expression of genes involved fatty acid metabolism and PPAR signaling pathways. Resvratrol-treated Wrn mutant mice also increased the expression of genes involved in steroid and cholesterol biosynthesis, xenobiotic metabolisms as well as inflammation. Finally, resveratrol improved insulin-resistance and the hyperglycemia but had no impact on dyslipidemia and mean life span of Wrn mutant mice. Microarray analyses were performed on the liver tissues of 9 months old mice. Four independent biological replicates of this experiment (wild type vs resveratrol treated Wrn helicase mutant mice) were carried out with a dye swap on two replicates of each genotype.

Dataset Information

Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional WRN mutant protein

Publications

Vitamin C alters the amount of specific endoplasmic reticulum associated proteins involved in lipid metabolism in the liver of mice synthesizing a nonfunctional Werner syndrome (Wrn) mutant protein.

Similar Datasets

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