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.