Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

SUBMITTER: Guido Hooiveld

PROVIDER: E-GEOD-17863 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

ACCESS DATA

Publications

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver.

Sanderson Linda M LM Degenhardt Tatjana T Koppen Arjen A Kalkhoven Eric E Desvergne Beatrice B Müller Michael M Kersten Sander S

Molecular and cellular biology 20091005 23

Peroxisome proliferator-activated receptor alpha (PPARalpha) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction between Wy14643 and fasting. Numerous genes were commonly regulated in liver between the two treatments, including many classical PPARalpha target genes, such as Aldh3a2 and Cpt2. Remarkably, several genes ...[more]

PMID: 19805517

Similar Datasets

Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

Project description:Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to explore the possible mechanisms involved. To that end, C57Bl/6 mice rendered obese and steatotic by chronic high-fat feeding were treated for 1 week with clodronate liposomes, which cause depletion of Kupffer cells. Loss of expression of marker genes Cd68, F4/80, and Clec4f, and loss of Cd68 immunostaining verified almost complete removal of Kupffer cells from the liver. Also, expression of complement components C1, the chemokine (C-C motif) ligand 6 (Ccl6), and cytokines interleukin-15 (IL-15) and IL-1beta were markedly reduced. Importantly, Kupffer cell depletion significantly decreased liver triglyceride and glucosylceramide levels concurrent with increased expression of genes involved in fatty acid oxidation including peroxisome proliferator-activated receptor alpha (PPARalpha), carnitine palmitoyltransferase 1A (Cpt1alpha), and fatty acid transport protein 2 (Fatp2). Treatment of mice with IL-1beta decreased expression of PPARalpha and its target genes, which was confirmed in primary hepatocytes. Consistent with these data, IL-1beta suppressed human and mouse PPARalpha promoter activity. Suppression of PPARalpha promoter activity was recapitulated by overexpression of nuclear factor kappaB (NF-kappaB) subunit p50 and p65, and was abolished upon deletion of putative NF-kappaB binding sites. Finally, IL-1beta and NF-kappaB interfered with the ability of PPARalpha to activate gene transcription. CONCLUSION: Our data point toward important cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage. The effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1beta, which suppresses PPARalpha expression and activity. Expression profiling of livers from mice fed control, low-fat diet diet or high-fat diet for 20weeks with or without knockdown of Kupffer cells.

Dataset Information

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

Publications

Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure