Transcriptional profiling reveals divergent roles of PPAR and PPAR / in regulation of gene expression in mouse liver

Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S. Transcriptional profiling reveals divergent roles of PPAR and PPAR / 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) / 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 pronounced, 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 / / 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 / mice, no changes in plasma free fatty acid, plasma -hydroxybutyrate, liver triglycerides, and liver glycogen were observed in PPAR / / 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.