Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA118629 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This is a phase 1/1b open label, multicenter dose escalation and dose expansion study to investigate the safety, tolerability and anti-tumor activity of TPST-1120, a small molecule selective antagonist of PPARα (peroxisome proliferator activated receptor alpha) as monotherapy and in combination with a systemic anticancer agent, nivolumab, an anti-PD1 antibody, in subjects with advanced solid tumors.
| 2296301 | ecrin-mdr-crc
Project description:The class 3 phosphoinositide 3-kinase (PI3K) is required for the lysosomal degradation by autophagy and vesicular trafficking, assuring adaptation to energy shortages. Mitochondrial lipid catabolism is another important energy source. Autophagy and mitochondrial metabolism are transcriptionally controlled by nutrient sensing nuclear receptors. However, it is not known whether the class 3 PI3K contributes to this regulation. Here we show that hepatocyte-specific inactivation of Vps15, the essential regulatory subunit of the class 3 PI3K, results in mitochondrial depletion and a failure to oxidize fatty acids. Mechanistically, the transcriptional activity of Peroxisome Proliferator Activated Receptor alpha (PPARα), a nuclear receptor that orchestrates fatty acid catabolism, is blunted in Vps15-deficient livers. We find PPARα transcriptional repressors Histone Deacetylase 3 (Hdac3) and Nuclear receptor co-repressor 1 (NCoR1) accumulated in Vps15-deficient livers due to defective autophagic flux. Pharmacologic activation of PPARα with a synthetic ligand, re-expression of its co-activator Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (PGC-1α) or inhibition of Hdac3 restored mitochondrial biogenesis and lipid oxidation in Vps15-deficient hepatocytes. These findings reveal a role for the class 3 PI3K and autophagy in transcriptional coordination of mitochondrial metabolism.
2020-02-06 | E-MTAB-7685 | biostudies-arrayexpress
Project description:The goal of this study was to determine short-term key event markers using qualitative and quantitative methods in an established pathway of mouse liver tumorigenesis mediated by peroxisome proliferator-activated receptor alpha (PPARα). a 7-day case study approach was used to determine transcriptional PODs and effect thresholds for early key events in an established MOA for liver tumorigenesis in mice. The target pathway is mediated by peroxisome proliferator-activated receptor alpha (PPARalpha) (Corton et al. 2013). In this study we analyzed three reference phthalates with different levels of receptor activity and liver outcomes at 2 years.
2015-11-03 | GSE64187 | GEO
Project description:Phosphatidylcholine transfer protein (PC-TP, a.k.a StarD2) is abundantly expressed in liver and is regulated by PPARα. When fed the synthetic PPARα ligand fenofibrate, Pctp-/- mice exhibited altered lipid and glucose homeostasis. Microarray profiling of liver from fenofibrate fed wild type and Pctp-/- mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. Because its expression controlled the transcriptional activities of both PPARα and HNF4α in cell culture, the broader impact of PC-TP on nutrient metabolism is most likely secondary to its role in fatty acid metabolism. 6 livers collected from PC-TP knockout mice fed a fenobrate-supplemented diet were used as the experimental group. 6 livers collected from wild type mice fed a fenofibrate-supplemented diet were used as the control group. RNA prepared from one liver was used to hybridize one GeneChip, so that there were 6 experimental GeneChips and 6 control GeneChips.
2010-08-12 | E-GEOD-17666 | biostudies-arrayexpress
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.
2013-12-18 | E-GEOD-53399 | biostudies-arrayexpress
Project description:Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic diseases globally and nonalcoholic steatohepatitis is its progressive stage with limited therapeutic options. Here a role for intestinal peroxisome proliferator-activated receptor α (PPARα)-fatty acid binding protein 1 (FABP1) in obesity-associated metabolic syndrome, fatty liver and nonalcoholic steatohepatitis via modulating dietary fat absorption was uncovered. Intestinal PPARα is highly activated accompanied by marked upregulation of FABP1 by high-fat diet (HFD) in mice and obese humans. Intestine-specific PPARα or FABP1 disruption in mice decreases HFD-induced obesity, fatty liver and nonalcoholic steatohepatitis and intestinal PPARα disruption fails to further decrease obesity and NASH. Chemical PPARα antagonism improves metabolic disorders depending on the presence of intestinal PPARα or FABP1. Translationally, GW6471 decreases human PPARα-driven intestinal fatty acid uptake and therapeutically improves obesity in PPARA-humanized, but not Ppara-null, mice. These results suggest that intestinal PPARα-FABP1 axis could be a therapeutic target for NASH.
2022-09-01 | GSE190140 | GEO
Project description:Phosphatidylcholine transfer protein (PC-TP, a.k.a StarD2) is abundantly expressed in liver and is regulated by PPARα. When fed the synthetic PPARα ligand fenofibrate, Pctp-/- mice exhibited altered lipid and glucose homeostasis. Microarray profiling of liver from fenofibrate fed wild type and Pctp-/- mice revealed differential expression of a broad array of metabolic genes, as well as their regulatory transcription factors. Because its expression controlled the transcriptional activities of both PPARα and HNF4α in cell culture, the broader impact of PC-TP on nutrient metabolism is most likely secondary to its role in fatty acid metabolism.
2010-08-12 | GSE17666 | GEO
Project description:Peroxisome-proliferator activated receptor α (PPARα) activation reprograms liver gene expression to support fatty acid oxidation during fasting. How PPARα engages in transcriptional programs coping with catabolic fasting responses is insufficiently understood. By applying a protein-protein interaction methodology that also captures transient interactions, we revealed the orphan nuclear receptor estrogen-related receptor α (ERRα) as a novel interaction partner of liganded PPARα and found that this interaction is enhanced following cellular nutrient starvation. Among target genes affected by PPARα-ERRα transcriptional crosstalk in fasted murine livers, multiple components of the electron transport chain were identified. Using pharmacological tools to study hepatic gene subsets under dual PPARα and ERRα control and moving from short-term to prolonged nutrient deprivation, we found that ERRα can switch from being a PPARα target gene suppressor to a marked PPARα target gene activator. Mechanistically, ERRα may control PPARα transcriptional activity via binding onto PPARα’s coactivator interaction site and via facilitating cofactor relays. In sum, a variety of crosstalk mechanisms between PPARα and ERRα seems to co-ordinately drive essential gene regulatory changes in the starving hepatocyte.
2024-04-01 | GSE200658 | GEO
Project description:Characterization of Peroxisome Proliferator-Activated Receptor alpha (PPAR(alpha)) - Independent Effects of PPAR(alpha) Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate Activates the Constitutive Activated Receptor data files in this series indicate the involvement of PPAR(alpha) and CAR regulatory pathway after DEHP treatment. Keywords: gene expression/microarray
2009-10-20 | GSE18564 | GEO
Project description:The majority of diabetics are susceptible to cardiac dysfunction and heart failure, while conventional drug therapy cannot correct diabetic cardiomyopathy (DCM) progression. Herein, we assessed the potential role and therapeutic value of ubiquitin-specific protease 28 (USP28) on the metabolic vulnerability of DCM. cardiac USP28 deficient diabetic mice showed cardiac dysfunction, lipid accumulation, and mitochondrial disarrangement, compared to their controls. Conversely, USP28 overexpression improved systolic and diastolic dysfunction and ameliorated cardiac hypertrophy and fibrosis in the diabetic heart. Mechanistically, USP28 directly interacted with peroxisome proliferator-activated receptor α (PPARα), deubiquitinating and stabilizing PPARα (Lys152) to promote mitofusin 2 (Mfn2) transcription, thereby impeding mitochondrial morphofunctional defects.
2023-10-15 | GSE244904 | GEO