Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver

Linda M Sanderson, Mark V Boekschoten, Beatrice Desvergne, Michael Müller, Sander Kersten

Research output: Contribution to journalArticlepeer-review

88 Citations (Scopus)

Abstract

Little is known about the role of the transcription factor peroxisome proliferator-activated receptor (PPAR) beta/delta in liver. Here we set out to better elucidate the function of PPARbeta/delta in liver by comparing the effect of PPARalpha and PPARbeta/delta deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARalpha and PPARbeta/delta deletion was similar, whereas in fasted state the effect of PPARalpha deletion was much more pronounced, consistent with the pattern of gene expression of PPARalpha and PPARbeta/delta. Minor overlap was found between PPARalpha- and PPARbeta/delta-dependent gene regulation in liver. Pathways upregulated by PPARbeta/delta deletion were connected to innate immunity and inflammation. Pathways downregulated by PPARbeta/delta deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARbeta/delta-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARbeta/delta target genes. In contrast to PPARalpha-/- mice, no changes in plasma free fatty acid, plasma beta-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPARbeta/delta-/- mice. Our data indicate that PPARbeta/delta governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver.
Original languageEnglish
Pages (from-to)42-52
Number of pages11
JournalPhysiological Genomics
Volume41
Issue number1
DOIs
Publication statusPublished - 3 Mar 2010

Keywords

  • Animals
  • Gene Deletion
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Immunity
  • Inflammation
  • Liver
  • Metabolome
  • Mice
  • Oligonucleotide Array Sequence Analysis
  • PPAR alpha
  • PPAR delta
  • PPAR-beta
  • Transcription, Genetic

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