Glucose or Altered Ceramide Biosynthesis Mediate Oxygen Deprivation Sensitivity Through Novel Pathways Revealed by Transcriptome Analysis in Caenorhabditis elegans

摘要

Individuals with type 2 diabetes display metabolic abnormalities, such as hyperglycemia, increased free fatty acids, insulin resistance, and altered ceramide levels, that contribute to vascular dysfunctions and compromised oxygen delivery. Caenorhabditis elegans fed a glucose-supplemented diet or with altered ceramide metabolism, due to a mutation, are sensitive to oxygen deprivation (anoxia). Our experiments showed that the combination of these factors further decreased the anoxia survival. RNA-sequencing analysis was performed to assess how a glucose-supplemented diet and/or a mutation altered the transcriptome. Comparison analysis of transcripts associated with anoxia-sensitive animals [() mutation or a glucose diet] revealed 199 common transcripts encoded by genes with known or predicted functions involving innate immunity, cuticle function (collagens), or xenobiotic and endobiotic phase I and II detoxification system. Use of RNA interference (RNAi) to target gene products of the xenobiotic and endobiotic phase I and II detoxification system (UDP-glycosyltransferase and Cytochrome p450 genes; , , , , , , , and ) increased anoxia survival in wild-type animals fed a standard diet. Anoxia sensitivity of the () animals was suppressed by RNAi of or genes. A glucose diet fed to the P0 hermaphrodite decreased the anoxia survival of its F1 embryos; however, the RNAi of href="http://www.wormbase.org/db/get?name=WBGene00015449;class=Gene" data-ga-action="click_feat_suppl" ref="reftype=extlink&article-id=5068937&issue-id=277481&journal-id=1684&FROM=Article%7CFront%20Matter&TO=External%7CLink%7CURI" target="_blank">ugt-63 and href="http://www.wormbase.org/db/get?name=WBGene00019967;class=Gene" data-ga-action="click_feat_suppl" ref="reftype=extlink&article-id=5068937&issue-id=277481&journal-id=1684&FROM=Article%7CFront%20Matter&TO=External%7CLink%7CURI" target="_blank">cyp-33C8 suppressed anoxia sensitivity. These studies provide evidence that the detoxification system impacts oxygen deprivation responses and that C. elegans can be used to model the conserved detoxification system.