RNA-seq of primary hepatocytes treated with GR and PPARalpha agonists in the presence of LPS
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB29192 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR2842680.fastq.gz | Fastqsanger.gz | |||
| ERR2842690.fastq.gz | Fastqsanger.gz | |||
| ERR2842700.fastq.gz | Fastqsanger.gz | |||
| ERR2842710.fastq.gz | Fastqsanger.gz | |||
| ERR2842720.fastq.gz | Fastqsanger.gz |
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Project description:RNA-seq of primary hepatocytes treated with GR and PPARalpha agonists in the presence of LPS
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Project description:The aim of the experiment was to identify genes regulated by 19 h treatment with 1 uM Dexamethasone (GR ligand) and 0,5 uM GW7647 (PPAR alpha ligand) in the LPS-induced (100 ng/ml 19 h) primary macrophages.
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Project description:The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist. Keywords: acute versus chronic treatment of piperidine PPARalpha agonists
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Project description:Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs), able to separate anti-inflammatory effects via gene suppression from metabolic effects via gene activation, have been unsuccessful so far. In this study, we characterized a set of functionally diverse GR ligands in A549 cells, first using a panel of luciferase-based reporter gene assays evaluating GR-driven gene activation and gene suppression. We expanded this minimal assay set with novel luciferase-based read-outs monitoring GR protein levels, GR dimerization and GR Serine 211 (Ser211) phosphorylation status and compared their outcomes with compound effects on the mRNA levels of known GR target genes in A549 cells and primary hepatocytes. We found that luciferase reporters evaluating GR-driven gene activation and gene repression were not always reliable predictors for effects on endogenous target genes. Remarkably, our novel assay monitoring GR Ser211 phosphorylation levels proved to be the most reliable predictor for compound effects on almost all tested endogenous GR targets, both driven by gene activation and repression. The integration of this novel assay in existing screening platforms may therefore increase chances to find novel GR ligands with an improved therapeutic benefit.
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Project description:The nuclear receptor PPARalpha is recognized as the primary target of the fibrate class of hypolipidemic drugs and mediates lipid lowering in part by activating a transcriptional cascade that induces genes involved in the catabolism of lipids. We report here the characterization of three novel PPARalpha agonists with therapeutic potential for treating dyslipidemia. These structurally related compounds display potent and selective binding to human PPARalpha and support robust recruitment of coactivator peptides in vitro. These compounds markedly potentiate chimeric transcription systems in cell-based assays and strikingly lower serum triglycerides in vivo. The transcription networks induced by these selective PPARalpha agonists were assessed by transcriptional profiling of mouse liver after acute and chronic treatment. The induction of several known PPARalpha target genes involved with fatty acid metabolism were observed, reflecting the expected pharmacology associated with PPARalpha activation. We also noted the downregulation of a number of genes related to immune cell function, the acute phase response, and glucose metabolism; suggesting that these compounds may have anti-inflammatory action in the mammalian liver. Taken together, these studies articulate the therapeutic promise of a selective PPARalpha agonist. Experiment Overall Design: Male C57Bl/6 mice (n=4 for all except 5 day treatment of 146-02 was n=2) were treated with the piperidine agonists for 24hr or 5 days at 1mg/kg/day, or water (vehicle) as control.
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Project description:Studies in mice have shown that PPARalpha is an important regulator of hepatic lipid metabolism and the acute phase response. However, little information is available on the role of PPARalpha in human liver. Here we set out to compare the function of PPARalpha in mouse and human hepatocytes via analysis of target gene regulation. Primary hepatocytes from 6 human and 6 mouse donors were treated with PPARalpha agonist Wy14643 and gene expression profiling was performed using Affymetrix GeneChips followed by a systems biology analysis. Baseline PPARalpha expression was similar in human and mouse hepatocytes. Depending on species and time of exposure, Wy14643 significantly induced the expression of 362-672 genes. Surprisingly minor overlap was observed between the Wy14643-regulated genes from mouse and human, although more substantial overlap was observed at the pathway level. Xenobiotics metabolism and apolipoprotein synthesis were specifically regulated by PPARalpha in human hepatocytes, whereas glycolysis-gluconeogenesis was regulated specifically in mouse hepatocytes. Most of the genes commonly regulated in mouse and human were involved in lipid metabolism and many represented known PPARalpha targets, including CPT1A, HMGCS2, FABP, ACSL, and ADFP. Several genes were identified that were specifically induced by PPARalpha in human (MBL2, ALAS1, CYP1A1, TSKU) or mouse (Fbp2, lgals4, Cd36, Ucp2, Pxmp4). Furthermore, several putative novel PPARalpha targets were identified that were commonly regulated in both species, including CREB3L3, KLF10, KLF11 and MAP3K8. Our results suggest that PPARalpha activation has a major impact on gene regulation in human hepatocytes. Importantly, the role of PPARalpha as master regulator of hepatic lipid metabolism is generally well-conserved between mouse and human. Overall, however, PPARalpha regulates a mostly divergent set of genes in mouse and human hepatocytes. Experiment Overall Design: Primary hepatocytes from 6 human subjects were treated with the PPARalpha agonist Wy14643 for 6 and 24 hours, and gene expression profiling was performed using Affymetrix GeneChips. Human hepatocytes and Hepatocyte Culture Medium Bulletkit were purchased from Lonza Bioscience (Verviers, Belgium). Primary hepatocytes were isolated from surgical liver biopsies obtained from six individual donors who underwent surgery after informed consent was obtained for surgery with subsequent use of samples in experiments. Hepatocytes were isolated with two-step collagenase perfusion method and the viability of the cells was over 80%. Cells were plated on collagen-coated six-well plates and filled with maintenance medium. Upon arrival of the cells, the medium was discarded and was replaced by Hepatocyte Culture Medium (HCM) with additives. The additives included Gentamicin sulphate/Amphotercin-B, Bovine serum albumin (Fatty acid free), Transferrin, Ascorbic acid, Insulin, Epidermal growth factor, Hydrocortisone hemisuccinate. The next day, cells were incubated in fresh medium in the presence or absence of Wy14643 (50 microM) dissolved in DMSO for 6 and 24 hours, followed by RNA isolation.
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