RNA-Seq of liver from CLA-exposed mice with/without PPARα antagonist
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA668069 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12794418_1.fastq.gz | Fastqsanger.gz | |||
| SRR12794418_2.fastq.gz | Fastqsanger.gz | |||
| SRR12794419_1.fastq.gz | Fastqsanger.gz | |||
| SRR12794419_2.fastq.gz | Fastqsanger.gz | |||
| SRR12794420_1.fastq.gz | Fastqsanger.gz |
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Project description:We demonstrate that conjugated linoleic acid (CLA), when given to mice as a dietary supplement, induced an enlarged liver and hepatic steatosis. The progression of NAFLD and insulin resistance was reversed by GW6471 a small-molecule antagonist of PPARα. Transcriptional profiling of livers unraveled that genes involved in lipid metabolism core gene programs controlled by PPARα in response to CLA and GW6471.Our findings reveal a novel role of PPARα in the regulation of lipid homeostasis and highlight its druggable nature in NAFLD.
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Project description:Autophagy is an evolutionally conserved catabolic process that recycles nutrients upon starvation and maintains cellular energy homeostasis1-3. Its acute regulation by nutrient sensing signaling pathways is well described, but its longer-term transcriptional regulation is not. The nuclear receptors PPARα and FXR are activated in the fasted or fed liver, respectively4,5. Here we show that both regulate hepatic autophagy. Pharmacologic activation of PPARα reverses the normal suppression of autophagy in the fed state, inducing autophagic lipid degradation, or lipophagy. This response is lost in PPARα knockout (PPARα-/-) mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor FXR strongly suppresses the induction of autophagy in the fasting state, and this response is absent in FXR knockout (FXR-/-) mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARα and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. These results reveal complementary, interlocking mechanisms for regulation of autophagy by nutrient status. Mouse liver PPARα cistromes in fed 8-week-old male WT or PPARα KO mice treated with or without its synthetic agonist ligand GW7647twice a day were generated by deep sequencing in quadruplicate using illumina
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Project description:Cis-9, trans-11-conjugated linoleic acid (c9, t11-CLA), a functional fatty acid, is one of the research hotspots in the fields of functional dairy products development because of its multiple beneficial effects in humans and animals. In milk, most c9, t11-CLA is de novo synthesized from trans-11-octadecenoic acid (TVA) and it is confirmed that genes such as stearoyl-coA desaturase 1 (SCD1) play a key role in the synthesis. However, few studies have been reported to deeply elucidate the SCD1-dependent molecular mechanism of cis9, trans11-CLA synthesis and its relationship with the pathways of energy metabolism and lipid metabolism. Therefore, in the present study, MAC-T cells were divided into three groups: CAY group (SCD1-inhibited MAC-T cell model with the addition of CAY, TVA), TVA group (only TVA), and Control group (without CAY, TVA). The relative mRNA expression of SCD1 was measured using real-time PCR, while TVA accumulation and c9, t11 -CLA synthesis were analyzed using gas chromatography (GC). The SCD1-related proteins were firstly screened in MAC-T cells by Tandem Mass Tag (TMT)-based quantitative proteomics analysis, then their functions were annotated by bioinformatic analysis, and finally their relationships with SCD1 were evaluated by parallel reaction monitoring (PRM) analysis and small RNA interference. The results showed that the deficiency of SCD1 led by CAY10566 blocked the synthesis of c9, t11-CLA in MAC-T cells. Sixty-one SCD1-associated proteins were screened and found to be mainly involved in the pathways of energy metabolism and lipid metabolism, such as glycolytic pathway, pentose phosphate pathway, fatty acid elongation pathway, and unsaturated fatty acid biosynthesis. Among these genes, 17 proteins were validated under the PRM analysis. PGAM1 (phosphoglycerate mutase 1), TPI1 (triosephosphate isomerase 1), LDHB (lactate dehydrogenase B), and ALDOA (aldolase, fructose-bisphosphate A) were verified to have a negative relationships with SCD1. This study furthered our understanding of the molecular mechanisms of c9, t11-CLA synthesis in the mammary glands of dairy cows.
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Project description:2,4-dinitrotoluene (2,4-DNT), a nitroaromatic used in industrial and explosive manufacturing processes, is known to contaminate artillery ranges, demilitarization areas and munitions manufacturing facilities. Previous transcriptomic and lipidomic studies identified energy metabolism as a principle biochemical process affected by 2,4-DNT where up-stream effects on PPARα signaling were hypothesized as themolecular initiating event for these effects. Here, the validity of this hypothetical adverse outcome pathway (AOP) was assessed by testing the hypothesis that 2,4-DNT-induced perturbations in PPARα signaling and resultant downstream deficits in energy metabolism, especially from lipids, would result in organism-level impacts on exercise endurance. PPARα knock-out (-/-) and wild-type (WT) mice were exposed for 14 days to vehicle or 2,4-DNT at a dose (134 mg/kg/day) that did not exhibit overt systemic toxicity. Mice performed an exercise challenge (forced swim) 1 day after the last dose. 2,4-DNT decreased swim times in WT and PPARα (-/-) mice, but the effect was significantly less in PPARα (-/-) mice indicating the critical of PPARα in mediating 2,4-DNT-induced energy metabolism deficits. 2,4-DNT caused down-regulation of transcripts involved in fatty acid metabolism, gluconeogenesis, triacylglycerol catabolism, and the pentose phosphate pathway, and 2,4-DNT treated wild-type mice had decreased serum trigylcerides and increased serum glucose versus 2,4-DNT treated PPARα (-/-) mice. Our results support the hypothesis that 2,4-DNT perturbs PPARα signaling as a molecular initiating event therefore impacting energy metabolism, especially lipid metabolism, producing reduced exercise endurance in mice. RNA was isolated from liver tissue of vehicle or 2,4-DNT treated wild-type or PPARα (-/-) mice (n=6) and RT-PCR performed to analyze genes involved in fatty acid metabolism
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Project description:To identify potential LXR target genes induced in the context of atherosclerosis we performed a transcriptomic analysis of human macrophages exposed or not to human carotid plaque homogenates in the presence or the absence of the LXR antagonist GSK 2033. We used primary macrophages from three distincts donors exposed to three differents plaque homogenates.
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Project description:Conjugated linoleic acid (CLA), a class of fatty acids found in beef and dairy products, has been shown to inhibit tumorigenesis in a variety of cancer model systems. Based on previously well-documented anti-tumor activity of CLA in rodent models of breast cancer, a pilot study was initiated to examine the effect of dietary CLA in a well-established transgenic model of breast cancer. Western blots were performed for the detection of AKT, c-Src, ERK1/2, and Cdc24. CLA significantly increased tumor burden (p<0.1) independent of an increase in oncogenic signaling. Mammary gland whole mounts indicated a loss of mammary adipose and extensive epithelial expansion in CLA-treated animals. Microarray analysis indicated a significant reduction in cytoskeletal related genes with at least a two-fold decrease in five out of six CLA-fed animals compared to untreated controls. Reduction of Cdc42, a key regulator of cell adhesion and cytoskeletal arrangements, was confirmed at the protein level by western blot (p<0.01). These findings suggest that dietary CLA may advance the malignant phenotype by promoting a loss of cell polarity and adhesion in the mammary gland epithelium. This action may have serious clinical implications for a subset high-risk population and warrants further investigation.
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Project description:Analysis of Helicobacter pylori strain 26695 after 20 minutes of 0.25μg/ml Clarithromycin. Results provide insight into the mechanisms employed by the bacterium that help it adapt to Clarithromycin stress In the study presented here, we compared the gene expression profile between H.pylori without CLA treatment and H.pylori treated with 0.25μg/ml Clarithromycin.
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Project description:Nuclear receptor activation in liver leads to coordinated alteration of the expression of multiple gene products with attendant phenotypic changes of hepatocytes. Peroxisome proliferators including endogenous fatty acids, environmental chemicals, and drugs induce a multi-enzyme metabolic response that affects lipid and fatty acid processing. We studied the signaling network for the peroxisome proliferator-associated receptor alpha (PPARα) in primary human hepatocytes using the selective PPARα ligand, GW7647. We measured gene expression over multiple concentrations and times and conducted ChIP-seq studies at 2 and 24 hours to assess genomic binding of PPARα. Over all treatments there were 192 genes differentially expressed. Of these only 51% showed evidence of PPARα binding – either directly at PPARα response elements or via alternative mechanisms. Almost half of regulated genes had no PPARα binding. We then developed two novel bioinformatics methods to visualize the dose-dependent activation of both the transcription factor circuitry for PPARα and the downstream metabolic network in relation to functional annotation categories. Available databases identified several key transcription factors involved with the non-genomic targets after GW7647 treatment, including SP1, STAT1, ETS1, ERα, and HNF4α. The linkage from PPARα binding through gene expression likely requires intermediate protein kinases to activate these transcription factors. We found enrichment of functional annotation categories for organic acid metabolism and cell lipid metabolism among the differentially expressed genes. Lipid transport processes showed enrichment at the highest concentration of GW7647 (10μM). While our strategy for mapping transcriptional networks is evolving, these approaches are necessary in moving from toxicogenomic methods that derive signatures of activity to methods that establish pathway structure, showing the coordination of the activated nuclear receptor with other signaling pathways. Primary hepatocytes from four donors were exposed to 0, 0.001, 0.01, 0.1, 1.0, or 10.0μM GW7647 for 2, 6, 12, 24, or 72 hours.
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