Hepatic Transcriptome Reveals That Fructose Downregulated Xenobiotics Metabolizing Enzymes Through Aryl Hydrocarbon Receptor Signaling Suppression in C57BL/6 N Mice (P15-011-19)

Abstract

ObjectivesFor decades, fructose intake has been recognized as an environmental risk for metabolic syndromes and diseases. Thus, we comprehensively examined the effects of fructose intake on mice liver transcriptomes. MethodsFructose supplemented water (34%; wt/vol) was fed to both male and female C57BL/6 N mice at their free will for six weeks, followed by hepatic transcriptomics analysis. Based on our criteria, differentially expressed genes (DEGs) were selected and subjected to further computational analyses to predict key pathways and upstream regulator(s). Subsequently, predicted genes and pathways from the transcriptomics dataset were validated via quantitative RT-PCR analyses. ResultsAs results, we identified 89 down-regulated and 88 up-regulated mRNAs in fructose-fed mice livers. These DEGs were subjected to bioinformatic analysis tools in which DEGs were mainly enriched in xenobiotic metabolic processes; further, in the Ingenuity Pathway Analysis software, it was suggested that the aryl hydrocarbon receptor (AhR) is an upstream regulator governing overall changes while fructose suppresses the AhR signaling pathway. In our quantitative RT-PCR validation, we confirmed that fructose suppressed AhR signaling through modulating expressions of transcription factor (arnt) and upstream regulators (ncor2, and rb1). ConclusionsAltogether, we demonstrated that ad libitum fructose intake suppresses the canonical AhR signaling pathway in C57BL/6 N mice liver. Based on our current observations, further studies are warranted, especially with regard to the effects of co-exposure to fructose on 1) other types of carcinogens and 2) inflammation inducing agents (or even diets such as a high-fat diet), to find implications of fructose induced-AhR suppression. Funding SourcesThis work was supported by the University of Arkansas, VPRED Start-up fund and Dale Bumpers College of Agricultural, Food and Life Sciences. Support has been also provided in part by the Arkansas Biosciences Institute, a partnership of scientists from Arkansas Children’s Hospital, Arkansas State University, the University of Arkansas-Division of Agriculture, the University of Arkansas, Fayetteville, and the University of Arkansas for Medical Sciences. The Arkansas Biosciences Institute is the major research component of the Arkansas Tobacco Settlement Proceeds Act of 2000. Supporting Tables, Images and/or Graphs▪▪