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

Sanderson LM, Boekschoten MV, Desvergne B, Muller M, Kersten S. Transcriptional profiling reveals divergent roles of PPAR alpha and PPAR beta/delta in regulation of gene expression in mouse liver. Physiol Genomics 41: 42-52, 2010. First published December 15, 2009; doi:10.1152/physiolgenomics.00127.2009.-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 PPAR beta/delta in liver by comparing the effect of PPAR alpha and PPAR beta/delta deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPAR alpha and PPAR beta/delta deletion was similar, whereas in fasted state the effect of PPAR alpha deletion was much more pronounced, consistent with the pattern of gene expression of PPAR alpha and PPAR beta/delta. Minor overlap was found between PPAR alpha- and PPAR beta/delta-dependent gene regulation in liver. Pathways upregulated by PPAR beta/delta deletion were connected to innate immunity and inflammation. Pathways downregulated by PPAR beta/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 PPAR beta/delta-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPAR beta/delta target genes. In contrast to PPAR alpha-/- mice, no changes in plasma free fatty acid, plasma beta-hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPAR beta/delta-/- mice. Our data indicate that PPAR beta/delta governs glucose utilization and lipoprotein metabolism and has an important anti-inflammatory role in liver. Overall, our analysis reveals divergent roles of PPAR alpha and PPAR beta/delta in regulation of gene expression in mouse liver.