mRNA profiling reveals divergent roles of PPARa and PPAR/d in regulating mouse liver gene expression (PPARb/d samples)

Little is known about the role of the transcription factor PPAR/d in liver. Here we set out to better elucidate the function of PPAR/d in liver by comparing the effect of PPARa and PPAR/d deletion using whole genome transcriptional profiling and analysis of plasma and liver metabolites. In fed state, the number of genes altered by PPARa and PPAR/d deletion was similar, whereas in fasted state the effect of PPARa deletion was much more pronounced, consistent with the pattern of gene expression of PPARa and PPAR/d. Minor overlap was found between PPARa- and PPAR/d-dependent gene regulation in liver. Pathways upregulated by PPAR/d deletion were connected to innate immunity. Pathways downregulated by PPAR/d 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/d-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPAR/d target genes. In contrast to PPARa-/- mice, no changes in plasma FFA, plasma -hydroxybutyrate, liver triglycerides and liver glycogen were observed in PPAR/d-/- mice. Our data indicate a role for PPAR/d in hepatic glucose utilization and lipoprotein metabolism but not in the adaptive response to fasting.

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Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S