mRNA profiling reveals divergent roles of PPARa and PPARß/d in regulating mouse liver gene expression (PPARa samples). Mus musculus

Little is known about the role of the transcription factor PPARß/d in liver. Here we set out to better elucidate the function of PPARß/d in liver by comparing the effect of PPARa and PPARß/d deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARa and PPARß/d deletion was similar, whereas in fasted state the effect of PPARa deletion was much more pronounced, consistent with the pattern of gene expression of PPARa and PPARß/d. Minor overlap was found between PPARa- and PPARß/d-dependent gene regulation in liver. Pathways upregulated by PPARß/d deletion were connected to innate immunity. Pathways downregulated by PPARß/d deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPARß/d-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARß/d target genes. In contrast to PPARa-/- mice, no changes in plasma FFA, plasma ß-hydroxybutyrate, liver triglycerides and liver glycogen were observed in PPARß/d-/- mice. Our data indicate a role for PPARß/d in hepatic glucose utilization and lipoprotein metabolism but not in the adaptive response to fasting. Keywords: Analysis of target gene regulation by using microarrays Overall design: Pure-bred Sv129 PPARα -/- mice and corresponding wildtype mice were used. Male mice (n=4-5 per group) were either fed or fasted for 24 hours. At the end of the experiment, mice were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%). Blood was collected by orbital puncture, after which the mice were sacrificed by cervical dislocation. Livers were dissected, snap frozen in liquid nitrogen and kept at -80ºC until further analysis. For RNA analyses, tissue from the same part of the liver lobe was used.