Little is known about the role of the transcription factor peroxisome proliferator-activated receptor (PPAR) ␤/␦ in liver. Here we set out to better elucidate the function of PPAR␤/␦ in liver by comparing the effect of PPAR␣ and PPAR␤/␦ deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPAR␣ and PPAR␤/␦ deletion was similar, whereas in fasted state the effect of PPAR␣ deletion was much more

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... consistent with the pattern of gene expression of PPAR␣ and PPAR␤/␦. Minor overlap was found between PPAR␣-and PPAR␤/ ␦-dependent gene regulation in liver. Pathways upregulated by PPAR␤/␦ deletion were connected to innate immunity and inflammation. Pathways downregulated by PPAR␤/␦ deletion included lipoprotein metabolism and various pathways related to glucose utilization, which correlated with elevated plasma glucose and triglycerides and reduced plasma cholesterol in PPAR␤/␦Ϫ/Ϫ mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPAR␤/␦ target genes. In contrast to PPAR␣Ϫ/Ϫ mice, no changes in plasma free fatty acid, plasma ␤-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPAR␤/␦Ϫ/Ϫ mice. Our data indicate that PPAR␤/␦ governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPAR␣ and PPAR␤/␦ in regulation of gene expression in mouse liver.