Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Peroxisome proliferator-activated receptor α mediates acute effects of palmitoylethanolamide on sensory neurons.

ABSTRACT: The amplitude of the depolarization-evoked Ca2+ transient is larger in dorsal root ganglion (DRG) neurons from tumor-bearing mice compared with that of neurons from naive mice, and the change is mimicked by coculturing DRG neurons with the fibrosarcoma cells used to generate the tumors (Khasabova et al., 2007). The effect of palmitoylethanolamide (PEA), a ligand for the peroxisome proliferator-activated receptor α (PPARα), was determined on the evoked-Ca2+ transient in the coculture condition. The level of PEA was reduced in DRG cells from tumor-bearing mice as well as those cocultured with fibrosarcoma cells. Pretreatment with PEA, a synthetic PPARα agonist (GW7647), or ARN077, an inhibitor of the enzyme that hydrolyzes PEA, acutely decreased the amplitude of the evoked Ca2+ transient in small DRG neurons cocultured with fibrosarcoma cells. The PPARα antagonist GW6471 blocked the effect of each. In contrast, the PPARα agonist was without effect in the control condition, but the antagonist increased the amplitude of the Ca2+ transient, suggesting that PPARα receptors are saturated by endogenous ligand under basal conditions. Effects of drugs on mechanical sensitivity in vivo paralleled their effects on DRG neurons in vitro. Local injection of ARN077 decreased mechanical hyperalgesia in tumor-bearing mice, and the effect was blocked by GW6471. These data support the conclusion that the activity of DRG neurons is rapidly modulated by PEA through a PPARα-dependent mechanism. Moreover, agents that increase the activity of PPARα may provide a therapeutic strategy to reduce tumor-evoked pain.

SUBMITTER: Khasabova IA

PROVIDER: S-EPMC3462371 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Hepatic peroxisome proliferator-activated receptor alpha mediates the major metabolic effects of Wy-14643.

Project description:Background and aimPeroxisome proliferator-activated receptor alpha (PPARα) is a molecular target of various fibrate drugs clinically used to lower serum lipids. However, the tissue-specific functions of PPARα remain to be elucidated. This study aimed to explore the tissue-specific functions of PPARα in response to Wy-14643.MethodsA hepatocyte-specific Ppara knockout mouse line was used to explore the impact of hepatic PPARα activity on the systemic response to treatment with the potent PPARα agonist Wy-14643.ResultsWy-14643 mainly activated hepatic PPARα and regulated the expression of PPARα target genes in liver. Hepatic Ppara disruption abolished the triglyceride lowering effects of Wy-14643, prevented agonist-induced hypophagia, and ablated PPARα target gene response in the liver.ConclusionsThese findings indicate that Wy-14643 treatment mainly activates hepatic PPARα, and the hypolipidemic and hypophagic effects of Wy-14643 are dependent on PPARα activation within hepatocytes.

| S-EPMC6334298 | biostudies-literature

Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis.

Project description:The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara -/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

| S-EPMC8382038 | biostudies-literature

Peroxisome proliferator-activated receptor-α accelerates α-chlorofatty acid catabolism.

Project description:α-Chlorofatty aldehydes are generated from myeloperoxidase-derived HOCl targeting plasmalogens, and are subsequently oxidized to α-chlorofatty acids (α-ClFAs). The catabolic pathway for α-ClFA is initiated by ω-oxidation. Here, we examine PPAR-α activation as a mechanism to increase α-ClFA catabolism. Pretreating both HepG2 cells and primary mouse hepatocytes with the PPAR-α agonist, pirinixic acid (Wy 14643), increased the production of α-chlorodicarboxylic acids (α-ClDCAs) in cells treated with exogenous α-ClFA. Additionally, α-ClDCA production in Wy 14643-pretreated wild-type mouse hepatocytes was accompanied by a reduction in cellular free α-ClFA. The dependence of PPAR-α-accelerated α-ClFA catabolism was further demonstrated by both impaired metabolism in mouse PPAR-α-/- hepatocytes and decreased clearance of plasma α-ClFA in PPAR-α-/- mice. Furthermore, Wy 14643 treatments decreased plasma 2-chlorohexadecanoic acid levels in wild-type mice. Additional studies showed that α-ClFA increases PPAR-α, PPAR-δ, and PPAR-γ activities, as well as mRNA expression of the PPAR-α target genes, CD36, CPT1a, Cyp4a10, and CIDEC. Collectively, these results indicate that PPAR-α accelerates important pathways for the clearance of α-ClFA, and α-ClFA may, in part, accelerate its catabolism by serving as a ligand for PPAR-α.

| S-EPMC5282948 | biostudies-literature

Regulation of peroxisome proliferator-activated receptor-alpha by MDM2.

Project description:Peroxisome proliferator-activated receptor-alpha (PPARalpha) belongs to the nuclear receptor (NR) family of transcription factors and regulates lipid and glucose metabolism. Like other NRs, the regulation of gene expression by PPARalpha depends on cofactor recruitment to the transcription complex and multiple protein-protein interactions. In this study, Murine Double Minute 2 (MDM2), an E3 ubiquitin ligase, is identified as a PPARalpha-interacting protein that regulates PPARalpha transcriptional activity. MDM2 modulated the transcriptional activity of PPARalpha and PPARbeta/delta, but not PPARgamma in reporter assays. Knockdown of MDM2 by small interfering RNA in rat hepatoma cells inhibited ligand-induced mRNA levels of several PPARalpha target genes involved in lipid metabolism. MDM2 associated with PPARalpha on target gene promoters, and this association increased in response to Wy14,643 treatment. MDM2 interacted with PPARalpha and this interaction occurred with the A/B domain of PPARalpha. Coexpression of MDM2 increased PPARalpha ubiquitination and the E3 ubiquitin ligase activity of MDM2 affected PPARalpha protein expression and transcriptional activity. MDM2 expression was decreased in response to clofibrate in wild-type (WT), but not in PPARalpha null mice, indicating a PPARalpha-dependent regulation. These studies identify a role for MDM2 in regulating PPARalpha-mediated pathways of lipid metabolism.

| S-EPMC2644403 | biostudies-literature

ChREBP mediates glucose repression of peroxisome proliferator-activated receptor alpha expression in pancreatic beta-cells.

Project description:Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic β-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of genes involved in fatty acid metabolism and has been shown to protect against lipid-induced β-cell dysfunction. We and others have previously shown that expression of the PPARα gene in β-cells is rapidly repressed by glucose. Here we show that the PPARα gene is transcribed from five alternative transcription start sites, resulting in three alternative first exons that are spliced to exon 2. Expression of all PPARα transcripts is repressed by glucose both in insulinoma cells and in isolated pancreatic islets. The observation that the dynamics of glucose repression of PPARα transcription are very similar to those of glucose activation of target genes by the carbohydrate response element-binding protein (ChREBP) prompted us to investigate the potential role of ChREBP in the regulation of PPARα expression. We show that a constitutively active ChREBP lacking the N-terminal domain efficiently represses PPARα expression in insulinoma cells and in rodent and human islets. In addition, we demonstrate that siRNA-mediated knockdown of ChREBP abrogates glucose repression of PPARα expression as well as induction of well established ChREBP target genes in insulinoma cells. In conclusion, this work shows that ChREBP is a critical and direct mediator of glucose repression of PPARα gene expression in pancreatic β-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of β-cells.

| S-EPMC3075668 | biostudies-literature

Molecular characterization of novel peroxisome proliferator-activated receptor alpha agonists

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

2008-11-25 | GSE12147 | GEO

Ligand-regulated heterodimerization of peroxisome proliferator-activated receptor α with liver X receptor α.

Project description:Peroxisome proliferator-activated receptor α (PPARα) and liver X receptor α (LXRα) are members of the nuclear receptor superfamily that function to regulate lipid metabolism. Complex interactions between the LXRα and PPARα pathways exist, including competition for the same heterodimeric partner, retinoid X receptor α (RXRα). Although data have suggested that PPARα and LXRα may interact directly, the role of endogenous ligands in such interactions has not been investigated. Using in vitro protein-protein binding assays, circular dichroism, and co-immunoprecipitation of endogenous proteins, we established that full-length human PPARα and LXRα interact with high affinity, resulting in altered protein conformations. We demonstrated for the first time that the affinity of this interaction and the resulting conformational changes could be altered by endogenous PPARα ligands, namely long chain fatty acids (LCFA) or their coenzyme A thioesters. This heterodimer pair was capable of binding to PPARα and LXRα response elements (PPRE and LXRE, respectively), albeit with an affinity lower than that of the respective heterodimers formed with RXRα. LCFA had little effect on binding to the PPRE but suppressed binding to the LXRE. Ectopic expression of PPARα and LXRα in mammalian cells yielded an increased level of PPRE transactivation compared to overexpression of PPARα alone and was largely unaffected by LCFA. Overexpression of both receptors also resulted in transactivation from an LXRE, with decreased levels compared to that of LXRα overexpression alone, and LCFA suppressed transactivation from the LXRE. These data are consistent with the hypothesis that ligand binding regulates heterodimer choice and downstream gene regulation by these nuclear receptors.

| S-EPMC4007980 | biostudies-literature

Hepatic Peroxisome Proliferator-Activated Receptor Alpha Dysfunction in Porcine Septic Shock.

Project description:Despite decades of research, sepsis remains one of the most urgent unmet medical needs. Mechanistic investigations into sepsis have mainly focused on targeting inflammatory pathways; however, recent data indicate that sepsis should also be seen as a metabolic disease. Targeting metabolic dysregulations that take place in sepsis might uncover novel therapeutic opportunities. The role of peroxisome proliferator-activated receptor alpha (PPARɑ) in liver dysfunction during sepsis has recently been described, and restoring PPARɑ signaling has proven to be successful in mouse polymicrobial sepsis. To confirm that such therapy might be translated to septic patients, we analyzed metabolic perturbations in the liver of a porcine fecal peritonitis model. Resuscitation with fluids, vasopressor, antimicrobial therapy and abdominal lavage were applied to the pigs in order to mimic human clinical care. By using RNA-seq, we detected downregulated PPARɑ signaling in the livers of septic pigs and that reduced PPARɑ levels correlated well with disease severity. As PPARɑ regulates the expression of many genes involved in fatty acid oxidation, the reduced expression of these target genes, concomitant with increased free fatty acids in plasma and ectopic lipid deposition in the liver, was observed. The results obtained with pigs are in agreement with earlier observations seen in mice and support the potential of targeting defective PPARɑ signaling in clinical research.

| S-EPMC9777423 | biostudies-literature

Salidroside Ameliorates Cardiomyocyte Hypertrophy by Upregulating Peroxisome Proliferator-Activated Receptor-α.

Project description:Cardiac hypertrophy is an adaptive change in response to pressure overload, however the hypertrophy may evolve toward heart failure if cannot be corrected as soon as possible. The dysfunction of peroxisome proliferator-activated receptor-α (PPARα) plays a key role in cardiac hypertrophy. In the present study, salidroside inhibited the mRNA expressions of hypertrophic markers including atrial natriuretic factor and brain natriuretic peptide in a dosage-dependent manner. Furthermore, the protein expression and transcriptional activity of PPARα were increased by salidroside in H9C2 cells treated with angiotensin II, as well as the target genes of PPARα, while the situations were nearly reversed when PPARα was knocked down. Next, salidroside could elevate the expression of ATGL, a key upstream regulator of PPARα; the effects of salidroside including increasing PPARα function and inhibiting cardiomyocyte hypertrophy were impaired by ATGL knockdown. Our present studies suggested that salidroside elevated PPARα function to alleviate cardiomyocyte hypertrophy, which was involved in the increase of ATGL expression.

| S-EPMC9035553 | biostudies-literature

Adaptation of peroxisome proliferator-activated receptor alpha to hibernation in bats.

Project description:BackgroundHibernation is a survival mechanism in the winter for some animals. Fat preserved instead of glucose produced is the primary fuel during winter hibernation of mammals. Many genes involved in lipid metabolism are regulated by the peroxisome proliferator-activated receptor alpha (PPARα). The role of PPARα in hibernation of mammals remains largely unknown. Using a multidisciplinary approach, we investigated whether PPARα is adapted to hibernation in bats.ResultsEvolutionary analyses revealed that the ω value of Pparα of the ancestral lineage of hibernating bats in both Yinpterochiroptera and Yangochiroptera was lower than that of non-hibernating bats in Yinpterochiroptera, suggesting that a higher selective pressure acts on Pparα in hibernating bats. PPARα expression was found to be increased at both mRNA and protein levels in distantly related bats (Rhinolophus ferrumequinum and Hipposideros armiger in Yinpterochiroptera and Myotis ricketti in Yangochiroptera) during their torpid episodes. Transcription factors such as FOXL1, NFYA, NFYB, SP1, TBP, and ERG were bioinformatically determined to have a higher binding affinity to the potential regulatory regions of Pparα in hibernating than in non-hibernating mammals. Genome-wide bioinformatic analyses of 64 mammalian species showed that PPARα has more potential target genes and higher binding affinity to these genes in hibernating than in non-hibernating mammals.ConclusionsWe conclude that PPARα is adapted to hibernation in bats based on the observations that Pparα has a more stringent functional constraint in the ancestral lineage of hibernating bats and a higher level of expression in hibernating than in non-hibernating bats. We also conclude that PPARα plays a very important role in hibernation as hibernators have more PPARα target genes than non-hibernators, and PPARα in hibernators has a higher binding affinity for its target genes than in non-hibernators.

| S-EPMC4435907 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data