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The peroxisome proliferator-activated receptor-β/δ antagonist GSK0660 mitigates retinal cell inflammation and leukostasis.
Capozzi ME, Savage SR, McCollum GW, Hammer SS, Ramos CJ, Yang R, Bretz CA, Penn JS
(2020) Exp Eye Res 190: 107885
MeSH Terms: Adult, Animals, Cells, Cultured, Cytokines, Endothelial Cells, Ependymoglial Cells, Humans, Inflammation, Leukostasis, Male, Mice, Mice, Inbred C57BL, PPAR delta, PPAR-beta, Palmitic Acids, Real-Time Polymerase Chain Reaction, Retina, Retinitis, Sulfones, Thiophenes
Show Abstract · Added March 30, 2020
Diabetic retinopathy (DR) is triggered by retinal cell damage stimulated by the diabetic milieu, including increased levels of intraocular free fatty acids. Free fatty acids may serve as an initiator of inflammatory cytokine release from Müller cells, and the resulting cytokines are potent stimulators of retinal endothelial pathology, such as leukostasis, vascular permeability, and basement membrane thickening. Our previous studies have elucidated a role for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in promoting several steps in the pathologic cascade in DR, including angiogenesis and expression of inflammatory mediators. Furthermore, PPARβ/δ is a known target of lipid signaling, suggesting a potential role for this transcription factor in fatty acid-induced retinal inflammation. Therefore, we hypothesized that PPARβ/δ stimulates both the induction of inflammatory mediators by Müller cells as well the paracrine induction of leukostasis in endothelial cells (EC) by Müller cell inflammatory products. To test this, we used the PPARβ/δ inhibitor, GSK0660, in primary human Müller cells (HMC), human retinal microvascular endothelial cells (HRMEC) and mouse retina. We found that palmitic acid (PA) activation of PPARβ/δ in HMC leads to the production of pro-angiogenic and/or inflammatory cytokines that may constitute DR-relevant upstream paracrine inflammatory signals to EC and other retinal cells. Downstream, EC transduce these signals and increase their synthesis and release of chemokines such as CCL8 and CXCL10 that regulate leukostasis and other cellular events related to vascular inflammation in DR. Our results indicate that PPARβ/δ inhibition mitigates these upstream (MC) as well as downstream (EC) inflammatory signaling events elicited by metabolic stimuli and inflammatory cytokines. Therefore, our data suggest that PPARβ/δ inhibition is a potential therapeutic strategy against early DR pathology.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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20 MeSH Terms
RNA-seq identifies a role for the PPARβ/δ inverse agonist GSK0660 in the regulation of TNFα-induced cytokine signaling in retinal endothelial cells.
Savage SR, McCollum GW, Yang R, Penn JS
(2015) Mol Vis 21: 568-76
MeSH Terms: Cells, Cultured, Chemokine CCL8, Cytokines, Endothelial Cells, Gene Expression Regulation, Humans, PPAR delta, PPAR-beta, Retinal Vessels, Sequence Analysis, RNA, Signal Transduction, Sulfones, Thiophenes, Tumor Necrosis Factor-alpha
Show Abstract · Added April 10, 2019
PURPOSE - The peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is a transcription factor with roles in metabolism, angiogenesis, and inflammation. It has yet undefined roles in retinal inflammation and diabetic retinopathy (DR). We used RNA-seq to better understand the role of the antagonist and inverse agonist of PPARβ/δ, GSK0660, in TNFα-induced inflammation. Understanding the underlying mechanisms of vascular inflammation could lead to new treatments for DR.
METHODS - RNA was isolated from human retinal microvascular endothelial cells treated with a vehicle, TNFα, or TNFα plus GSK0660. RNA-seq was performed with a 50 bp single read protocol. The differential expression was determined using edgeR and gene ontology, and a pathway analysis was performed using DAVID. RNA-seq validation was performed using qRT-PCR using the primers for ANGPTL4, CCL8, NOV, CXCL10, and PDPK1.
RESULTS - TNFα differentially regulated 1,830 transcripts, many of which are involved in the cytokine-cytokine receptor interaction, chemokine signaling, and inflammatory response. Additionally, TNFα highly upregulated genes involved in leukocyte recruitment, including CCL5, CX3CL1, and CXCL10. GSK0660 differentially regulated 273 transcripts in TNFα-treated cells compared to TNFα alone. A pathway analysis revealed the enrichment of cytokine-cytokine receptor signaling. In particular, GSK0660 blocks the TNFα-induced upregulation of CCL8, a chemokine involved in leukocyte recruitment.
CONCLUSIONS - TNFα regulates several genes related to retinal leukostasis in retinal endothelial cells. GSK0660 blocks the effect of TNFα on the expressions of cytokines involved in leukocyte recruitment, including CCL8, CCL17, and CXCL10 and it may therefore block TNFα-induced retinal leukostasis.
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MeSH Terms
A diurnal serum lipid integrates hepatic lipogenesis and peripheral fatty acid use.
Liu S, Brown JD, Stanya KJ, Homan E, Leidl M, Inouye K, Bhargava P, Gangl MR, Dai L, Hatano B, Hotamisligil GS, Saghatelian A, Plutzky J, Lee CH
(2013) Nature 502: 550-4
MeSH Terms: Acetyl-CoA Carboxylase, Animals, Circadian Rhythm, Diabetes Mellitus, Fatty Acids, Gene Expression Regulation, Homeostasis, Lipids, Lipogenesis, Liver, Male, Mice, Mice, Inbred C57BL, Muscles, Obesity, PPAR delta, Phosphatidylcholines, Principal Component Analysis
Show Abstract · Added September 6, 2016
Food intake increases the activity of hepatic de novo lipogenesis, which mediates the conversion of glucose to fats for storage or use. In mice, this program follows a circadian rhythm that peaks with nocturnal feeding and is repressed by Rev-erbα/β and an HDAC3-containing complex during the day. The transcriptional activators controlling rhythmic lipid synthesis in the dark cycle remain poorly defined. Disturbances in hepatic lipogenesis are also associated with systemic metabolic phenotypes, suggesting that lipogenesis in the liver communicates with peripheral tissues to control energy substrate homeostasis. Here we identify a PPARδ-dependent de novo lipogenic pathway in the liver that modulates fat use by muscle via a circulating lipid. The nuclear receptor PPARδ controls diurnal expression of lipogenic genes in the dark/feeding cycle. Liver-specific PPARδ activation increases, whereas hepatocyte-Ppard deletion reduces, muscle fatty acid uptake. Unbiased metabolite profiling identifies phosphatidylcholine 18:0/18:1 (PC(18:0/18:1) as a serum lipid regulated by diurnal hepatic PPARδ activity. PC(18:0/18:1) reduces postprandial lipid levels and increases fatty acid use through muscle PPARα. High-fat feeding diminishes rhythmic production of PC(18:0/18:1), whereas PC(18:0/18:1) administration in db/db mice (also known as Lepr(-/-)) improves metabolic homeostasis. These findings reveal an integrated regulatory circuit coupling lipid synthesis in the liver to energy use in muscle by coordinating the activity of two closely related nuclear receptors. These data implicate alterations in diurnal hepatic PPARδ-PC(18:0/18:1) signalling in metabolic disorders, including obesity.
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18 MeSH Terms
Peroxisome proliferator-activated receptor-β/δ regulates angiogenic cell behaviors and oxygen-induced retinopathy.
Capozzi ME, McCollum GW, Savage SR, Penn JS
(2013) Invest Ophthalmol Vis Sci 54: 4197-207
MeSH Terms: Angiogenesis Inhibitors, Animals, Cells, Cultured, Disease Models, Animal, Endothelial Cells, Humans, Oxygen, PPAR delta, PPAR-beta, Rats, Retinal Diseases, Retinal Neovascularization, Retinal Vessels, Sulfones, Thiazoles, Thiophenes
Show Abstract · Added October 9, 2013
PURPOSE - To develop new therapies against ocular neovascularization (NV), we tested the effect of peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ) agonism and antagonism on angiogenic behaviors and in human retinal microvascular endothelial cells (HRMEC) and on preretinal NV in rat oxygen-induced retinopathy (OIR).
METHODS - HRMECs were treated with the PPAR-β/δ agonist GW0742 and the antagonist GSK0660. Messenger RNA levels of a PPAR-β/δ target gene, angiopoietin-like-4 (angptl4) were assayed by qRT-PCR. HRMEC proliferation and tube formation were assayed according to standard protocols. OIR was induced in newborn rats by exposing them to alternating 24-hour episodes of 50% and 10% oxygen for 14 days. OIR rats were treated with GW0742 or GSK0660. Angptl4 protein levels were assessed by ELISA and preretinal NV was quantified by adenosine diphosphatase staining.
RESULTS - GW0742 significantly increased angptl4 mRNA, and GSK0660 significantly decreased angptl4 mRNA. GW0742 had no effect on HRMEC proliferation, but caused a significant and dose-responsive increase in tube formation. GSK0660 significantly reduced serum-induced HRMEC proliferation and tube formation in a dose-dependent manner. Intravitreal injection of GW0742 significantly increased total retinal Angptl4 protein, but intravitreal injection of GSK0660 had no effect. Intravitreal injection of GW0742 significantly increased retinal NV, as did GW0742 administered by oral gavage. Conversely, both intravitreal injection and intraperitoneal injection of GSK0660 significantly reduced retinal NV.
CONCLUSIONS - PPAR-β/δ activation exacerbates, and its inhibition reduces, preretinal NV. PPAR-β/δ may regulate preretinal NV through a prodifferentiation/maturation mechanism that depends on Angptl4. Pharmacologic inhibition of PPAR-β/δ may provide a rational basis for therapeutic targeting of ocular NV.
1 Communities
1 Members
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16 MeSH Terms
Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPARδ) in mice leads to increased susceptibility to diet-induced obesity.
Kocalis HE, Turney MK, Printz RL, Laryea GN, Muglia LJ, Davies SS, Stanwood GD, McGuinness OP, Niswender KD
(2012) PLoS One 7: e42981
MeSH Terms: Animals, Body Composition, Brain, Diet, Fat-Restricted, Diet, High-Fat, Eating, Energy Metabolism, Female, Lipid Metabolism, Male, Mice, Mice, Knockout, Obesity, PPAR delta
Show Abstract · Added December 10, 2013
Central nervous system (CNS) lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO). Peroxisome proliferator-activated receptors (PPAR α, δ, γ) are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPARα and/or PPARγ may contribute to weight gain and obesity. PPARδ is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPARδ increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARδ protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD), accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPARδ. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD), yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPARγ and target genes of both PPARα and PPARγ, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.
4 Communities
4 Members
1 Resources
14 MeSH Terms
Peroxisome proliferator-activated receptor delta (PPARD) genetic variation and type 2 diabetes in middle-aged Chinese women.
Villegas R, Williams S, Gao Y, Cai Q, Li H, Elasy T, Cai H, Edwards T, Xiang YB, Zheng W, Long J, Ou Shu X
(2011) Ann Hum Genet 75: 621-9
MeSH Terms: Adult, Aged, Asian Continental Ancestry Group, Body Mass Index, Diabetes Mellitus, Type 2, Female, Genome-Wide Association Study, Humans, Middle Aged, Motor Activity, PPAR delta, Polymorphism, Single Nucleotide
Show Abstract · Added December 10, 2013
Animal studies have shown that the peroxime proliferator-activated receptor delta (PPARD) gene regulates glucose metabolism and insulin sensitivity. Genetic variation in the PPARD gene might affect physical endurance and has been associated with obesity. We investigated the independent and modifying effect of variants in the PPARD gene with exercise participation and body mass index (BMI) on type 2 diabetes (T2D), using data from a genome-wide association study (GWAS) of middle-aged women living in Shanghai, China, with 1019 T2D cases and 1709 controls. The genotyping was performed using the Affymetrix Genome-Wide Human SNP Array 6.0 platform. Imputation was used to determine missing genotypes. Participation in exercise was assessed by a questionnaire. Anthropometric variables were measured by trained interviewers. The association between polymorphisms and T2D was assessed by logistic regression analyses. The combined effects of polymorphisms in the PPARD gene with exercise participation and BMI on T2D risk was assessed by conducting stratified analysis with exercise participation and BMI categories. No significant associations between PPARD and T2D were found in either genotyped or imputed SNPs and no effect modification between exercise participation and PPARD genetic variation was found, suggesting that PPARD is not a risk factor for T2D in this population.
© 2011 The Authors Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.
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12 MeSH Terms
β-Catenin and p120 mediate PPARδ-dependent proliferation induced by Helicobacter pylori in human and rodent epithelia.
Nagy TA, Wroblewski LE, Wang D, Piazuelo MB, Delgado A, Romero-Gallo J, Noto J, Israel DA, Ogden SR, Correa P, Cover TL, Peek RM
(2011) Gastroenterology 141: 553-64
MeSH Terms: Adenocarcinoma, Animals, Antigens, Bacterial, Bacterial Proteins, Catenins, Cell Proliferation, Cell Transformation, Neoplastic, Cells, Cultured, Cyclin E, Epithelial Cells, Gastric Mucosa, Gerbillinae, Helicobacter Infections, Helicobacter pylori, Humans, Ki-67 Antigen, Oncogene Proteins, PPAR delta, Signal Transduction, Stomach Neoplasms, beta Catenin
Show Abstract · Added July 26, 2012
BACKGROUND & AIMS - Colonization of gastric mucosa by Helicobacter pylori leads to epithelial hyperproliferation, which increases the risk for gastric adenocarcinoma. One H pylori virulence locus associated with cancer risk, cag, encodes a secretion system that transports effectors into host cells and leads to aberrant activation of β-catenin and p120-catenin (p120). Peroxisome proliferator-activated receptor (PPAR)δ is a ligand-activated transcription factor that affects oncogenesis in conjunction with β-catenin. We used a carcinogenic H pylori strain to define the role of microbial virulence constituents and PPARδ in regulating epithelial responses that mediate development of adenocarcinoma.
METHODS - Gastric epithelial cells or colonies were co-cultured with the H pylori cag(+) strain 7.13 or cagE(-), cagA(-), soluble lytic transglycosylase(-), or cagA(-)/soluble lytic transglycosylase(-) mutants. Levels of PPARδ and cyclin E1 were determined by real-time, reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy; proliferation was measured in 3-dimensional culture. PPARδ and Ki67 expression were determined by immunohistochemical analysis of human biopsies and rodent gastric mucosa.
RESULTS - H pylori induced β-catenin- and p120-dependent expression and activation of PPARδ in gastric epithelial cells, which were mediated by the cag secretion system substrates CagA and peptidoglycan. H pylori stimulated proliferation in vitro, which required PPARδ-mediated activation of cyclin E1; H pylori did not induce expression of cyclin E1 in a genetic model of PPARδ deficiency. PPARδ expression and proliferation in rodent and human gastric tissue was selectively induced by cag(+) strains and PPARδ levels normalized after eradication of H pylori.
CONCLUSIONS - The H pylori cag secretion system activates β-catenin, p120, and PPARδ, which promote gastric epithelial cell proliferation via activation of cyclin E1. PPARδ might contribute to gastric adenocarcinoma development in humans.
Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.
1 Communities
5 Members
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21 MeSH Terms
Peroxisome proliferator-activated receptor beta/delta expression and activation in lung cancer.
Pedchenko TV, Gonzalez AL, Wang D, DuBois RN, Massion PP
(2008) Am J Respir Cell Mol Biol 39: 689-96
MeSH Terms: Adult, Aged, Aged, 80 and over, Apoptosis, Cell Adhesion, Cell Line, Tumor, Cell Proliferation, Cell Survival, Cyclooxygenase 2, Female, Humans, Immunohistochemistry, Ligands, Lung, Lung Neoplasms, Male, Middle Aged, PPAR delta, PPAR-beta, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Signal Transduction, Tissue Array Analysis
Show Abstract · Added March 5, 2014
Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a ligand-binding inducible transcriptional factor linked to carcinogenesis. Important functions of PPARbeta/delta were demonstrated in series of human epithelial cancers; however, its role in lung cancer remains controversial. We investigated the differential expression level and localization of PPARbeta/delta in tumors and adjacent normal lung tissue, and the effect of PPARbeta/delta activation on lung cancer cell proliferation and apoptosis. PPARbeta/delta was expressed in all studied human non-small cell lung cancers, and strong PPARbeta/delta immunoreactivity was observed in epithelial cells of more than 75% of studied lung tumors. PPARbeta/delta expression was consistently limited to the cancer cells in tumor tissue, while in adjacent normal lung tissue it was limited predominantly to the mononuclear cells. We found that ligand-binding activation of PPARbeta/delta stimulates cell proliferation (an effect that was blocked by a dominant-negative construct of PPARbeta/delta), stimulates anchorage-independent cell growth, and inhibits apoptosis in lung cancer cell lines. Importantly, the activation of PPARbeta/delta induces Akt phosphorylation correlated with up-regulation of PDK1, down-regulation of PTEN, and increased expression of Bcl-xL and COX-2. These findings indicate that PPARbeta/delta exerts proliferative and anti-apoptotic effects via PI3K/Akt1 and COX-2 pathways. In conclusion, PPARbeta/delta is strongly expressed in the majority of lung cancers, and its activation induces proliferative and survival response in non-small cell lung cancer.
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23 MeSH Terms
Extracellular signal-regulated kinase is a target of cyclooxygenase-1-peroxisome proliferator-activated receptor-delta signaling in epithelial ovarian cancer.
Daikoku T, Tranguch S, Chakrabarty A, Wang D, Khabele D, Orsulic S, Morrow JD, Dubois RN, Dey SK
(2007) Cancer Res 67: 5285-92
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cell Growth Processes, Cell Line, Tumor, Cyclooxygenase 1, Cyclooxygenase Inhibitors, Enzyme Activation, Epithelial Cells, Epoprostenol, Female, Humans, Male, Mice, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Ovarian Neoplasms, PPAR delta, Pyrazoles, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
The underlying causes of epithelial ovarian cancer (EOC) are unclear, and treatment options for patients with advanced disease are limited. There is evidence that the use of nonsteroidal anti-inflammatory drugs is associated with decreased risk of developing EOC. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase (COX)-1 and COX-2, which catalyze prostaglandin biosynthesis. We previously showed that mouse and human EOCs have increased levels of COX-1, but not COX-2, and a COX-1-selective inhibitor, SC-560, attenuates prostaglandin production and tumor growth. However, the downstream targets of COX-1 signaling in EOC are not yet known. To address this question, we evaluated peroxisome proliferator-activated receptor delta (PPARdelta) expression and function in EOC. We found that EOC cells express high levels of PPARdelta, and neutralizing PPARdelta function reduces tumor growth in vivo. More interestingly, aspirin, a nonsteroidal anti-inflammatory drug that preferentially inhibits COX-1, compromises PPARdelta function and cell growth by inhibiting extracellular signal-regulated kinases 1/2, members of the mitogen-activated protein kinase family. Our study, for the first time, shows that whereas PPARdelta can be a target of COX-1, extracellular signal-regulated kinase is a potential target of PPARdelta. The ability of aspirin to inhibit EOC growth in vivo is an exciting finding because of its low cost, lack of cardiovascular side effects, and availability.
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21 MeSH Terms
Epidermal lipoxygenase products of the hepoxilin pathway selectively activate the nuclear receptor PPARalpha.
Yu Z, Schneider C, Boeglin WE, Brash AR
(2007) Lipids 42: 491-7
MeSH Terms: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid, 8,11,14-Eicosatrienoic Acid, Arachidonate Lipoxygenases, Cell Differentiation, Cell Line, Epidermal Cells, Epidermis, Genes, Reporter, Humans, Hydroxyeicosatetraenoic Acids, Lipoxygenase, Luciferases, PPAR alpha, PPAR delta, PPAR gamma, Receptors, Cytoplasmic and Nuclear, Signal Transduction
Show Abstract · Added December 10, 2013
Arachidonic acid can be transformed into a specific epoxyalcohol product via the sequential action of two epidermal lipoxygenases, 12R-LOX and eLOX3. Functional impairment of either lipoxygenase gene (ALOX12B or ALOXE3) results in ichthyosis, suggesting a role for the common epoxyalcohol product or its metabolites in the differentiation of normal human skin. Here we tested the ability of products derived from the epidermal LOX pathway to activate the peroxisome proliferator-activated receptors PPARalpha, gamma, and delta, which have been implicated in epidermal differentiation. Using a dual luciferase reporter assay in PC3 cells, the 12R-LOX/eLOX3-derived epoxyalcohol, 8R-hydroxy-11R,12R-epoxyeicosa-5Z,9E,14Z-trienoic acid, activated PPARalpha with similar in potency to the known natural ligand, 8S-hydroxyeicosatetraenoic acid (8S-HETE) (both at 10 microM concentration). In contrast, the PPARgamma and PPARdelta receptor isoforms were not activated by the epoxyalcohol. Activation of PPARalpha was also observed using the trihydroxy hydrolysis products (trioxilins) of the unstable epoxyalcohol. Of the four trioxilins isolated and characterized, the highest activation was observed with the isomer that is also formed by enzymatic hydrolysis of the epoxyalcohol. Formation of a ligand for the nuclear receptor PPARalpha may be one possibility by which 12R-LOX and eLOX3 contribute to epidermal differentiation.
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17 MeSH Terms