Crosstalk between CYP2E1 and PPARα substrates and agonists modulate adipose browning and obesity
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA798014 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR17643439_1.fastq.gz | Fastqsanger.gz | |||
| SRR17643439_2.fastq.gz | Fastqsanger.gz | |||
| SRR17643440_1.fastq.gz | Fastqsanger.gz | |||
| SRR17643440_2.fastq.gz | Fastqsanger.gz | |||
| SRR17643441_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:We report the discrepancy of hepatic mRNA expression in Cyp2e1 widetype and knockout mice by application of RNA-seq technology.
2022-06-01 | GSE193796 | GEO
Project description:Although the functions of metabolic enzymes and nuclear receptors in controlling physiological homeostasis have been established, their crosstalk in modulating metabolic disease has not been explored. Genetic ablation of the xenobiotic-metabolizing cytochrome P450 enzyme CYP2E1 in mice markedly induced adipose browning and increased energy expenditure to improve obesity. CYP2E1 deficiency activated the expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) target genes, including fibroblast growth factor (FGF) 21, that upon release from the liver, enhanced adipose browning and energy expenditure to decrease obesity. Nineteen metabolites were increased in Cyp2e1-null mice as revealed by global untargeted metabolomics, among which four compounds, lysophosphatidylcholine and three polyunsaturated fatty acids were found to be directly metabolized by CYP2E1 and to serve as PPARα agonists, thus explaining how CYP2E1 deficiency causes hepatic PPARα activation through increasing cellular levels of endogenous PPARα agonists. Translationally, a CYP2E1 inhibitor was found to activate the PPARα-FGF21-beige adipose axis and decrease obesity in wild-type mice, but not in liver-specific Ppara-null mice. The present results establish a metabolic crosstalk between PPARα and CYP2E1 that supports the potential for a novel anti-obesity strategy of activating adipose tissue browning by targeting the CYP2E1 to modulate endogenous metabolites beyond its canonical role in xenobiotic-metabolism.
| S-EPMC9136617 | biostudies-literature
Project description:To investigate the effect of Cyp2e1 and EtOH on mRNA expression in mouse tissues, we profiled total RNA expression using mouse tissues from Cyp2e1 -/- mice and Cyp2e1 +/+ mice upon EtOH fed mice compared to control. We compare the expression level of RNA and profile circular RNA expression using circular RNA junction.
2024-06-30 | GSE206348 | GEO
Project description:Chronic cold exposure causes white adipose tissue (WAT) to adopt features of brown adipose tissue, a process known as browning. Previous studies have hinted at a possible role for the transcription factor Peroxisome Proliferator-Activated Receptor alpha (PPARα) in cold-induced browning. Here we aimed to investigate the importance of PPARα in driving transcriptional changes during cold-induced browning in mice. Male wildtype and PPARα−/− mice were housed at thermoneutrality (28 °C) or cold (5 °C) for 10 days. Whole genome expression analysis was performed on inguinal WAT. In addition, other analyses were carried out. Whole genome expression data of livers of wildtype and PPARα−/− mice fasted for 24 h served as positive control for PPARα-dependent gene regulation.Cold exposure increased food intake and decreased weight of BAT and WAT to a similar extent in wildtype and PPARα−/− mice. Except for plasma non-esterified fatty acids, none of the cold-induced changes in plasma metabolites were dependent on PPARα genotype. Histological analysis of inguinal WAT showed clear browning upon cold exposure but did not reveal any morphological differences between wildtype and PPARα−/− mice. Transcriptomics analysis of inguinal WAT showed a marked effect of cold on overall gene expression, as revealed by principle component analysis and hierarchical clustering. However, wildtype and PPARα−/− mice clustered together, even after cold exposure, indicating a similar overall gene expression profile in the two genotypes. Pathway analysis revealed that cold upregulated pathways involved in energy usage, oxidative phosphorylation, and fatty acid β-oxidation to a similar extent in wildtype and PPARα−/− mice. Furthermore, cold-mediated induction of genes related to thermogenesis such as Ucp1, Elovl3, Cox7a1, Cox8, and Cidea, as well as many PPAR target genes, was similar in wildtype and PPARα−/− mice. Finally, pharmacological PPARα activation had a minimal effect on expression of cold-induced genes in murine WAT.Cold-induced changes in gene expression in inguinal WAT are unaltered in mice lacking PPARα, indicating that PPARα is dispensable for cold-induced browning.
2018-02-10 | GSE110420 | GEO
Project description:Despite significant advancements in cancer immunotherapy, many patients continue to respond poorly. Novel therapeutic strategies and drugs are urgently needed. Here, we found that CYP2E1 is significantly upregulated in M2 macrophages. The CYP2E1 inhibitor, Q11, could inhibit M2 macrophage polarization, while CYP2E1 overexpression could promote it. Increased levels of CYP2E1 and M2 macrophages in the tumor microenvironment of HCC patients correlate with poor prognosis. Q11 could inhibit tumor cells by targeting M2 macrophages rather than directly attacking tumor cells. Both Q11 and Cyp2e1 knockout could effectively suppress tumor growth. Q11 reduces the production of CYP2E1 metabolites (±)9(10)-DiHOME and (±)12(13)-DiHOME, thus attenuating PPARγ activation and M2 macrophage polarization. In summary, our findings suggest that Q11 could suppress M2 macrophage polarization by modulating the CYP2E1/(±)9(10)-DiHOME or (±)12(13)-DiHOME/PPARγ axis, indicating that CYP2E1 inhibition may be a novel therapeutic strategy for HCC and positioning Q11 as a promising therapeutic agent.
2024-12-26 | GSE282907 | GEO
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
2014-09-27 | E-GEOD-61817 | biostudies-arrayexpress
Project description:Total RNA-seq using mouse tissues from Cyp2e1 +/+ mice upon pair-fed, Cyp2e1 +/+ mice upon EtOH-fed, Cyp2e1 -/- mice upon pair-fed, and Cyp2e1 -/- mice upon EtOH fed.
| PRJNA850373 | ENA
Project description:Atherogenic dyslipidemia and chronic inflammation appear strongly associated with residual cardiovascular disease (CVD) risk. Peroxisome proliferator-activated receptor α (PPARα) agonists, which exert both triglyceride-lowering and anti-inflammatory properties, are potential therapeutic candidates to target residual CVD risk. However, CVD outcome studies with these drugs have yielded mixed results for currently unclear reasons. Thus, we performed single-nucleus RNA sequencing (snRNA-seq) to better understand the hepatic-specific molecular actions of PPARα and their distal effects on atherosclerotic plaque development. Hepatic PPARα activation limits a pro-inflammatory phenotype in hepatocytes and reduces leukocyte recruitment. This study highlights a non-lipid, anti-inflammatory mechanism of hepatic PPARα with implications for cardiovascular disease modulation.
2025-05-28 | GSE295990 | GEO
Project description:Hypoxic conditions in high-altitude environments present unique physiological stressors that drive metabolic adaptations, including adipose tissue browning. In this study, we investigated whether hypoxia (11.6% O₂, simulating 5,300 m altitude) could independently induce browning of adipose tissue in mice, apart from cold-induced mechanisms. Hypoxia significantly promoted the formation of multilocular adipocytes in inguinal white adipose tissue (iWAT) and upregulated thermogenic genes (UCP1, PGC-1α, Cox4i1, VEGF), glucose metabolism-related genes (IRS1/2, PDK2, PPARα), and beige adipocyte markers (Car4, UCP1). In contrast, interscapular brown adipose tissue (iBAT) showed minimal response to hypoxia, with no significant change in UCP1 expression. Notably, hypoxia elevated both Nrg4 and phosphorylated ErbB4 in iWAT. In vitro, Nrg4 overexpression in 3T3-L1 adipocytes increased the expression of PKAcα, PGC-1α, and UCP1, while pharmacological inhibition of ErbB4 phosphorylation using Dacomitinib attenuated Nrg4- and hypoxia-induced browning and lipolysis. In vivo, Dacomitinib treatment impaired hypoxia-mediated improvements in WAT browning and glucose tolerance. To explore the structural basis of this interaction, molecular docking and 100-ns molecular dynamics simulations were conducted, revealing strong and stable binding between Nrg4 and ErbB4, with calculated binding energies of −174.26 kcal/mol (MM/GBSA) and −19.5 kcal/mol (PRODIGY). These findings collectively demonstrate that the Nrg4–ErbB4 axis plays a central role in mediating hypoxia-induced browning and metabolic reprogramming of WAT, providing mechanistic insight into adipose tissue plasticity under low-oxygen conditions.
2025-06-11 | GSE298931 | GEO
Project description:The objective of the study was to examine changes in gene expression induced by CYP2E1 knockdown in neural progenitor cells.There were 6samples in total.Samples shs_1, shs_2, and shs_3 are the control group, and shCYP2E1_1, shCYP2E1_2, and shCYP2E1_3 are the CYP2E1 knockdown group.Neural progenitor cells were cultured in vitro from normal fetal brain tissue aborted at 21 weeks, infected with CYP2E1_shRNAs and CYP2E1_shRNA lentivirus respectively, and then differentiated and cultured for 4 days.The total RNA of each sample was extracted from the lentivirus infected, early differentiated human neural progenitor cells with TRIzol reagent.Then the RNA samples were processed for high throughput transcriptome sequencing on Illumina HiSeq 3000 platform.
2025-08-31 | GSE278691 | GEO