Transcriptional profiling reveals divergent roles of PPARa and PPARß/d in regulation of gene expression in mouse liver

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