Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver

Abstract

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