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

ABSTRACT: Little is known about the role of the transcription factor PPARß/d in liver. Here we set out to better elucidate the function of PPARß/d in liver by comparing the effect of PPARa and PPARß/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 PPARß/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 PPARß/d. Minor overlap was found between PPARa- and PPARß/d-dependent gene regulation in liver. Pathways upregulated by PPARß/d deletion were connected to innate immunity. Pathways downregulated by PPARß/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 PPARß/d-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARß/d target genes. In contrast to PPARa-/- mice, no changes in plasma FFA, plasma ß-hydroxybutyrate, liver triglycerides and liver glycogen were observed in PPARß/d-/- mice. Our data indicate a role for PPARß/d in hepatic glucose utilization and lipoprotein metabolism but not in the adaptive response to fasting. Keywords: Analysis of target gene regulation by using microarrays

ORGANISM(S): Mus musculus

PROVIDER: GSE17864 | GEO | 2009/12/29

SECONDARY ACCESSION(S): PRJNA123551

REPOSITORIES: GEO

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Project description:Little is known about the role of the transcription factor PPARÃ?/d in liver. Here we set out to better elucidate the function of PPARÃ?/d in liver by comparing the effect of PPARa and PPARÃ?/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 PPARÃ?/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 PPARÃ?/d. Minor overlap was found between PPARa- and PPARÃ?/d-dependent gene regulation in liver. Pathways upregulated by PPARÃ?/d deletion were connected to innate immunity. Pathways downregulated by PPARÃ?/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 PPARÃ?/d-/- mice. Downregulated genes that may underlie these metabolic alterations included Pklr, Fbp1, Apoa4, Vldlr, Lipg, and Pcsk9, which may represent novel PPARÃ?/d target genes. In contrast to PPARa-/- mice, no changes in plasma FFA, plasma Ã?-hydroxybutyrate, liver triglycerides and liver glycogen were observed in PPARÃ?/d-/- mice. Our data indicate a role for PPARÃ?/d in hepatic glucose utilization and lipoprotein metabolism but not in the adaptive response to fasting. Keywords: Analysis of target gene regulation by using microarrays Pure-bred Sv129 PPARÎ± -/- mice and corresponding wildtype mice were used. Male mice (n=4-5 per group) were either fed or fasted for 24 hours. At the end of the experiment, mice were anaesthetized with a mixture of isofluorane (1.5%), nitrous oxide (70%) and oxygen (30%). Blood was collected by orbital puncture, after which the mice were sacrificed by cervical dislocation. Livers were dissected, snap frozen in liquid nitrogen and kept at -80ÂºC until further analysis. For RNA analyses, tissue from the same part of the liver lobe was used.

Project description:Recent studies have reported that glycosphingolipids (GSL) might be involved in obesity induced insulin resistance. Those reports suggested that inhibition of GSL biosynthesis in animals ameliorated insulin sensitivity accompanied with improved glycemic control leading to decreased liver steatosis in obese mice. In addition, GSL depletion altered hepatic secretory function. In those studies, ubiquitously acting inhibitors for GSL-biosynthesis have been used to inhibit function of the enzyme Ugcg (UDP-glucose:ceramide glucosyltransferase), catalyzing the first step of the glucosylceramide based GSL-synthesis pathway. In the present study, a genetic approach for GSL deletion in hepatocytes was chosen to achieve full inhibition of GSL synthesis and to prevent possible adverse effects caused by Ugcg-inhibitors. Using the Cre/loxP system under control of the albumin promoter, GSL biosynthesis in hepatocytes and their release into the plasma could be effectively blocked. Deletion of GSL in hepatocytes did not change quantity of bile excretion through the biliary duct. Total bile salt content in bile-, feces- and plasma from mutant mice showed no difference as compared to control animals. Cholesterol concentration in liver-, bile-, feces- and plasma-samples remained unaffected. Lipoprotein concentration in plasma-samples in mutant animals reached similar levels as in their control littermates. No alteration in glucose tolerance after intraperitoneal application of glucose and insulin appeared in mutant animals. A preventive effect of GSL-deficiency on development of liver steatosis after high fat diet feeding could not be observed. Conclusion: The data suggest that GSL in hepatocytes are not essential for sterol, glucose and lipoprotein metabolism and do not prevent high fat diet-induced liver steatosis, indicating that Ugcg inhibitors exert their effect on hepatocytes either independently of GSL or mediated by other (liver) cell types. Comparison of wildtype mouse liver function versus Ugcg-deficient

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

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