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Sample records for dual peroxisome proliferator-activated

  1. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons.

    PubMed

    Tenenbaum, Alexander; Motro, Michael; Fisman, Enrique Z

    2005-01-01

    There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs--the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan--(alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of metabolic

  2. The dual peroxisome proliferator-activated receptor alpha/delta agonist GFT505 exerts anti-diabetic effects in db/db mice without peroxisome proliferator-activated receptor gamma-associated adverse cardiac effects.

    PubMed

    Hanf, Rémy; Millatt, Lesley J; Cariou, Bertrand; Noel, Benoit; Rigou, Géraldine; Delataille, Philippe; Daix, Valérie; Hum, Dean W; Staels, Bart

    2014-11-01

    We report here the efficacy and safety of GFT505, a novel liver-targeted peroxisome proliferator-activated receptor alpha/delta (PPARα/δ) agonist, in the db/db mouse model of diabetes. Mice were treated with vehicle, GFT505, PPARγ agonist rosiglitazone or dual-PPARα/γ agonist aleglitazar for up to 8 weeks. All compounds comparably reduced fasting glycaemia and HbA1c and improved insulin sensitivity. The glucose-lowering effect of GFT505 was associated with decreased hepatic gluconeogenesis, correlating with reduced expression of gluconeogenic genes. In contrast with the PPARγ-activating drugs, treatment with GFT505 did not affect heart weight and did not increase plasma adiponectin concentrations. This absence of cardiac effects of GFT505 was confirmed after 12 months of administration in cynomolgus monkeys, by the absence of echocardiographic and histological findings. Moreover, long-term GFT505 administration to monkeys induced no change in haematological parameters or in bone marrow differential cell counts. Compared to PPARγ-activating drugs, the dual-PPARα/δ agonist GFT505 therefore shows an improved benefit/risk ratio, treating multiple features of type 2 diabetes without inducing the cardiac side-effects associated with PPARγ activation.

  3. Peroxisome proliferator-activated receptor {alpha}-independent peroxisome proliferation

    SciTech Connect

    Zhang Xiuguo; Tanaka, Naoki . E-mail: naopi@hsp.md.shinshu-u.ac.jp; Nakajima, Takero; Kamijo, Yuji; Gonzalez, Frank J.; Aoyama, Toshifumi

    2006-08-11

    Hepatic peroxisome proliferation, increases in the numerical and volume density of peroxisomes, is believed to be closely related to peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) activation; however, it remains unknown whether peroxisome proliferation depends absolutely on this activation. To verify occurrence of PPAR{alpha}-independent peroxisome proliferation, fenofibrate treatment was used, which was expected to significantly enhance PPAR{alpha} dependence in the assay system. Surprisingly, a novel type of PPAR{alpha}-independent peroxisome proliferation and enlargement was uncovered in PPAR{alpha}-null mice. The increased expression of dynamin-like protein 1, but not peroxisome biogenesis factor 11{alpha}, might be associated with the PPAR{alpha}-independent peroxisome proliferation at least in part.

  4. Peroxisome proliferator-activated receptors and angiogenesis.

    PubMed

    Biscetti, F; Straface, G; Pitocco, D; Zaccardi, F; Ghirlanda, G; Flex, A

    2009-12-01

    The peroxisome proliferator-activated receptors (PPARs) are a group of three nuclear receptor isoforms, PPARalpha, PPARgamma and PPARdelta, encoded by different genes, and they form a subfamily of the nuclear receptor superfamily. The clinical interest in PPARs originates with fibrates and thiazolidinediones, which, respectively, act on PPARalpha and PPARgamma and are used to ameliorate hyperlipidaemia and hyperglycaemia in subjects with type 2 diabetes mellitus (T2DM). PPARs play a central role in these patients due to their ability to regulate the expression of numerous genes involved in glycaemic control, lipid metabolism, vascular tone and inflammation. Abnormal angiogenesis is implicated in several of the long-term complications of diabetes mellitus, characterized by vasculopathy associated with aberrant growth of new blood vessels. This pathological process plays a crucial role in diabetic retinopathy, nephropathy and neuropathy, impaired wound healing and impaired coronary collateral vessel development. In recent years, there has been increasing appreciation of the fact that PPARs might be involved in the molecular mechanisms that regulate angiogenesis through the action of growth factors and cytokines that stimulate migration, proliferation and survival of endothelial cells. During the last few years direct comparative analyses have been performed, using selective PPARs agonists, to clarify the angiogenic properties of the different members of the PPAR family. Lately, the findings provide new information to order to understand the biological, clinical and therapeutic effects of PPARs, and the role of these nuclear receptors in angiogenesis, with potentially important implications for the management of subjects affected by T2DM. PMID:19628379

  5. Therapeutic potential of the dual peroxisome proliferator activated receptor (PPAR)α/γ agonist aleglitazar in attenuating TNF-α-mediated inflammation and insulin resistance in human adipocytes.

    PubMed

    Massaro, Marika; Scoditti, Egeria; Pellegrino, Mariangela; Carluccio, Maria Annunziata; Calabriso, Nadia; Wabitsch, Martin; Storelli, Carlo; Wright, Matthew; De Caterina, Raffaele

    2016-05-01

    Adipose tissue inflammation is a mechanistic link between obesity and its related sequelae, including insulin resistance and type 2 diabetes. Dual ligands of peroxisome proliferator activated receptor (PPAR)α and γ, combining in a single molecule the metabolic and inflammatory-regulatory properties of α and γ agonists, have been proposed as a promising therapeutic strategy to antagonize adipose tissue inflammation. Here we investigated the effects of the dual PPARα/γ agonist aleglitazar on human adipocytes challenged with inflammatory stimuli. Human Simpson-Golabi-Behmel syndrome (SGBS) adipocytes were treated with aleglitazar or - for comparison - the selective agonists for PPARα or γ fenofibrate or rosiglitazone, respectively, for 24h before stimulation with TNF-α. Aleglitazar, at concentrations as low as 10nmol/L, providing the half-maximal transcriptional activation of both PPARα and PPARγ, reduced the stimulated expression of several pro-inflammatory mediators including interleukin (IL)-6, the chemokine CXC-L10, and monocyte chemoattractant protein (MCP)-1. Correspondingly, media from adipocytes treated with aleglitazar reduced monocyte migration, consistent with suppression of MCP-1 secretion. Under the same conditions, aleglitazar also reversed the TNF-α-mediated suppression of insulin-stimulated ser473 Akt phosphorylation and decreased the TNF-α-induced ser312 IRS1 phosphorylation, two major switches in insulin-mediated metabolic activities, restoring glucose uptake in insulin-resistant adipocytes. Such effects were similar to those obtainable with a combination of single PPARα and γ agonists. In conclusion, aleglitazar reduces inflammatory activation and dysfunction in insulin signaling in activated adipocytes, properties that may benefit diabetic and obese patients. The effect of aleglitazar was consistent with dual PPARα and γ agonism, but with no evidence of synergism. PMID:26976796

  6. Ombuin-3-O-β-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β

    SciTech Connect

    Malek, Mastura Abd; Hoang, Minh-Hien; Jia, Yaoyao; Lee, Ji Hae; Jun, Hee Jin; Lee, Dong-Ho; Lee, Hak Ju; Lee, Chul; Lee, Myung Koo; Hwang, Bang Yeon; Lee, Sung-Joon

    2013-01-25

    Highlights: ► Ombuin-3-O-β-D-glucopyranoside is a dual ligand for PPARα and δ/β. ► Ombuin-3-O-β-D-glucopyranoside reduces cellular lipid levels in multiple cell types. ► Cells stimulated with ombuine up-regulated target genes in cholesterol efflux. ► Cells stimulated with ombuine regulated target fatty acid β-oxidation and synthesis. ► Ombuin-3-O-β-D-glucopyranoside could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: We demonstrated that ombuin-3-O-β-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/β. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/β but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/β. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/β with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.

  7. Quantitative determination of MK-0767, a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist, in human plasma by liquid chromatography-tandem mass spectrometry.

    PubMed

    Song, Hengchang; Yan, Kerri; Xu, Xiaohui; Lo, Man-Wai

    2004-10-15

    5-[2,4-Dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[(4-trifluoromethyl)-phenyl]methyl]benzamide (I, MK-0767 or KRP-297, Fig. 1), is a dual alpha/gamma peroxisome proliferator-activated receptor (PPAR) agonist. A LC-MS/MS method for the determination of I in human plasma has been successfully developed, validated and applied to clinical programs. The analyte and internal standard (II) are extracted from 0.05 mL plasma via solid phase extraction (SPE). HPLC is used for the separation of I and II from possible co-extracted endogenous and other compounds. Detection is by MS/MS in multiple reaction monitoring (MRM) mode using a TurboIonSpray probe. The whole sample preparation is automated by using a Packard Multiprobe liquid handling system. The linear range is 4-2000 ng/mL in plasma. Recoveries were 71.1% and 69.4% for I and II, respectively. The method exhibited good linearity, reproducibility and sensitivity, selectivity and robustness when used for the analysis of clinical samples.

  8. Design and synthesis of benzoxazole containing indole analogs as peroxisome proliferator-activated receptor-γ/δ dual agonists.

    PubMed

    Gim, Hyo Jin; Cheon, Ye-Jin; Ryu, Jae-Ha; Jeon, Raok

    2011-05-15

    A series of benzoxazole or benzothiazole containing indole analogs, 6-alkoxyindole-2-carboxylic acids and 5-alkoxy-3-indolylacetic acids, were synthesized as novel candidates of PPARγ/δ dual agonists and their ligand activities for PPAR subtypes (α, γ, and δ) were investigated. In transient transactivation assay, several compounds activated PPARγ and δ with little activity of PPARα. Putative binding mode of the compounds 1a and 2a in the active site of PPARγ was similar with that of rosiglitazone and the molecular modeling provides molecular insight to the observed activity.

  9. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    PubMed

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation. PMID:22269613

  10. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease.

    PubMed

    Azhar, Salman

    2010-09-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/ß and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  11. Open tubular columns containing the immobilized ligand binding domain of peroxisome proliferator-activated receptors α and γ for dual agonists characterization by frontal affinity chromatography with MS detection

    PubMed Central

    Temporini, C.; Pochetti, G.; Fracchiolla, G.; Piemontese, L.; Montanari, R.; Moaddel, R.; Laghezza, A.; Altieri, F.; Cervoni, L.; Ubiali, D.; Prada, E.; Loiodice, F.; Massolini, G.; Calleri, E.

    2013-01-01

    The peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily. In the last years novel PPARs ligands have been identified and these include PPARα/γ dual agonists. To rapidly identify novel PPARs dual ligands, a robust binding assay amenable to high-throughput screening towards PPAR isoforms would be desirable. In this work we describe a parallel assay based on the principles of Frontal Affinity Chromatography coupled to Mass Spectrometry (FAC-MS) that can be used to characterize dual agonists. For this purpose the ligand binding domain of PPARα receptor was immobilized onto the surface of open tubular capillaries to create new PPAR-alpha-OT columns to be used in parallel with PPAR-gamma-OT columns. The two biochromatographic systems were used in both ranking and Kd experiments towards new ureidofibrate-like dual agonists for subtype selectivity ratio determination. In order to validate the system, the Kd values determined by frontal analysis chromatography were compared to the affinity constants obtained by ITC experiments. The results of this study strongly demonstrate the specific nature of the interaction of the ligands with the two immobilized receptor subtypes. PMID:23466198

  12. Peroxisome proliferator-activated receptors in the cardiovascular system

    PubMed Central

    Bishop-Bailey, David

    2000-01-01

    Peroxisome proliferator-activated receptor (PPAR)s are a family of three nuclear hormone receptors, PPARα, -δ, and -γ, which are members of the steriod receptor superfamily. The first member of the family (PPARα) was originally discovered as the mediator by which a number of xenobiotic drugs cause peroxisome proliferation in the liver. Defined functions for all these receptors, until recently, mainly concerned their ability to regulate energy balance, with PPARα being involved in β-oxidation pathways, and PPARγ in the differentiation of adipocytes. Little is known about the functions of PPARδ, though it is the most ubiquitously expressed. Since their discovery, PPARs have been shown to be expressed in monocytes/macrophages, the heart, vascular smooth muscle cells, endothelial cells, and in atherosclerotic lesions. Furthermore, PPARs can be activated by a vast number of compounds including synthetic drugs, of the clofibrate, and anti-diabetic thiazoldinedione classes, polyunsaturated fatty acids, and a number of eicosanoids, including prostaglandins, lipoxygenase products, and oxidized low density lipoprotein. This review will aim to introduce the field of PPAR nuclear hormone receptors, and discuss the discovery and actions of PPARs in the cardiovascular system, as well as the source of potential ligands. PMID:10696077

  13. Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

    SciTech Connect

    Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad

    2013-03-07

    Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

  14. Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility.

    PubMed

    Vitti, Maurizio; Di Emidio, Giovanna; Di Carlo, Michela; Carta, Gaspare; Antonosante, Andrea; Artini, Paolo Giovanni; Cimini, Annamaria; Tatone, Carla; Benedetti, Elisabetta

    2016-01-01

    Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed. PMID:27559343

  15. Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility.

    PubMed

    Vitti, Maurizio; Di Emidio, Giovanna; Di Carlo, Michela; Carta, Gaspare; Antonosante, Andrea; Artini, Paolo Giovanni; Cimini, Annamaria; Tatone, Carla; Benedetti, Elisabetta

    2016-01-01

    Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed.

  16. Peroxisome Proliferator-Activated Receptors in Female Reproduction and Fertility

    PubMed Central

    Carta, Gaspare; Artini, Paolo Giovanni

    2016-01-01

    Reproductive functions may be altered by the exposure to a multitude of endogenous and exogenous agents, drug or environmental pollutants, which are known to affect gene transcription through the peroxisome proliferator-activated receptors (PPARs) activation. PPARs act as ligand activated transcription factors and regulate metabolic processes such as lipid and glucose metabolism, energy homeostasis, inflammation, and cell proliferation and differentiation. All PPARs isotypes are expressed along the hypothalamic-pituitary-gonadal axis and are strictly involved in reproductive functions. Since female fertility and energy metabolism are tightly interconnected, the research on female infertility points towards the exploration of potential PPARs activating/antagonizing compounds, mainly belonging to the class of thiazolidinediones (TZDs) and fibrates, as useful agents for the maintenance of metabolic homeostasis in women with ovarian dysfunctions. In the present review, we discuss the recent evidence about PPARs expression in the hypothalamic-pituitary-gonadal axis and their involvement in female reproduction. Finally, the therapeutic potential of their manipulation through several drugs is also discussed. PMID:27559343

  17. Peroxisomes in cardiomyocytes and the peroxisome / peroxisome proliferator-activated receptor-loop.

    PubMed

    Colasante, Claudia; Chen, Jiangping; Ahlemeyer, Barbara; Baumgart-Vogt, Eveline

    2015-03-01

    It is well established that the heart is strongly dependent on fatty acid metabolism. In cardiomyocytes there are two distinct sites for the β-oxidisation of fatty acids: the mitochondrion and the peroxisome. Although the metabolism of these two organelles is believed to be tightly coupled, the nature of this relationship has not been fully investigated. Recent research has established the significant contribution of mitochondrial function to cardiac ATP production under normal and pathological conditions. In contrast, limited information is available on peroxisomal function in the heart. This is despite these organelles harbouring metabolic pathways that are potentially cardio-protective, and findings that patients with peroxisomal diseases, such as adult Refsum´s disease, can develop heart failure. In this article, we provide a comprehensive overview on the current knowledge of peroxisomes and the regulation of lipid metabolism by PPARs in cardiomyocytes. We also present new experimental evidence on the differential expression of peroxisome-related genes in the heart chambers and demonstrate that even a mild peroxisomal biogenesis defect (Pex11α-/-) can induce profound alterations in the cardiomyocyte´s peroxisomal compartment and related gene expression, including the concomitant deregulation of specific PPARs. The possible impact of peroxisomal dysfunction in the heart is discussed and a model for the modulation of myocardial metabolism via a peroxisome/PPAR-loop is proposed.

  18. Human peroxisome proliferator-activated receptor mRNA and protein expression during development

    EPA Science Inventory

    The peroxisome proliferator-activated receptors (PPAR) are nuclear hormone receptors that regulate lipid and glucose homeostasis and are important in reproduction and development. PPARs are targets ofpharmaceuticals and are also activated by environmental contaminants, including ...

  19. Regulation of Proteome Maintenance Gene Expression by Activators of Peroxisome Proliferator-Activated Receptor a (PPARa)

    EPA Science Inventory

    The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) is activated by a large number of xenobiotic and hypolipidemic compounds called peroxisome proliferator chemicals (PPC). One agonist of PPARa (WY-14,643) regulates responses in the mouse liver to chemic...

  20. Recent progress in research on peroxisome proliferator-activated receptor alpha-selective ligands.

    PubMed

    Miyachi, Hiroyuki

    2004-08-01

    The understanding of the functions of the nuclear receptor peroxisome proliferator-activated receptor a (PPARalpha) as a regulator of lipid and lipoprotein homeostasis, and the rapid development of parallel high-throughput screening assays to evaluate the activity toward other PPAR subtypes (PPARdelta and PPARgamma), have provided an opportunity to develop novel PPARalpha-selective, PPARalpha/gamma dual and PPAR pan agonists for the treatment of various metabolic diseases. This review focuses on the molecular pharmacology of PPARalpha, and summarizes recent literature and patent applications disclosing medicinal chemistry strategies to identify new PPARalpha-selective agonists. The species selectivity of some classes of PPARalpha-selective agonists in response to in vitro PPARalpha transactivation activity is also reported. PMID:15334308

  1. Novel Oxazolidinone-Based Peroxisome Proliferator Activated Receptor Agonists: Molecular Modeling, Synthesis, and Biological Evaluation.

    PubMed

    Fresno, N; Macías-González, M; Torres-Zaguirre, A; Romero-Cuevas, M; Sanz-Camacho, P; Elguero, J; Pavón, F J; Rodríguez de Fonseca, F; Goya, P; Pérez-Fernández, R

    2015-08-27

    A series of new peroxisome proliferator activated receptors (PPARs) chiral ligands have been designed following the accepted three-module structure comprising a polar head, linker, and hydrophobic tail. The majority of the ligands incorporate the oxazolidinone moiety as a novel polar head, and the nature of the hydrophobic tail has also been varied. Docking studies using the crystal structure of an agonist bound to the ligand binding domain of the PPARα receptor have been performed as a tool for their design. Suitable synthetic procedures have been developed, and compounds with different stereochemistries have been prepared. Evaluation of basal and ligand-induced activity proved that several compounds showed agonist activity at the PPARα receptor, thus validating the oxazolidinone template for PPAR activity. In addition, two compounds, 2 and 4, showed dual PPARα/PPARγ agonism and interesting food intake reduction in rats.

  2. Selective peroxisome proliferator-activated receptorα modulators (SPPARMα): The next generation of peroxisome proliferator-activated receptor α-agonists

    PubMed Central

    2013-01-01

    Dyslipidemia is a major risk factor for cardiovascular (CV) disease – the primary cause of death, worldwide. Although reducing levels of low-density lipoprotein-cholesterol can significantly reduce CV risk, a high level of residual risk persists, especially in people with obesity-related conditions, such as metabolic syndrome and type 2 diabetes mellitus. Peroxisome proliferator-activated receptor alpha- (PPARα-) agonists (e.g. fibrates), play a central role in the reduction of macro- and microvascular risk in these patients. However, the currently available fibrates are weak (PPARα-agonists) with limited efficacy due to dose-related adverse effects. To address this problem, a new generation of highly potent and selective PPARα-modulators (SPPARMα) is being developed that separate the benefits of the PPARα-agonists from their unwanted side effects. Among these, aleglitazar (a dual PPARα/γ agonist) and GFT505 (a dual PPAR α/δ agonist) have recently entered late-phase development. Although both compounds are more potent PPARα-activators than fenofibrate in vitro, only aleglitezar is more effective in lowering triglycerides and raising high-density lipoprotein-cholesterol (HDL-C) in humans. However, it is also associated with a potential risk of adverse effects. More recently, a highly potent, specific PPARα-agonist (K-877) has emerged with SPPARMα characteristics. Compared to fenofibrate, K-877 has more potent PPARα-activating efficacy in vitro, greater effects on triglycerides- and HDL-C levels in humans, and a reduced risk of adverse effects. If successful, K-877 has the potential to supersede the fibrates as the treatment of choice for patients with residual CV risk associated with metabolic syndrome and type 2 diabetes. PMID:23721199

  3. Dual targeting of peroxisomal proteins

    PubMed Central

    Ast, Julia; Stiebler, Alina C.; Freitag, Johannes; Bölker, Michael

    2013-01-01

    Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed. PMID:24151469

  4. Dual targeting of peroxisomal proteins.

    PubMed

    Ast, Julia; Stiebler, Alina C; Freitag, Johannes; Bölker, Michael

    2013-10-18

    Cellular compartmentalization into organelles serves to separate biological processes within the environment of a single cell. While some metabolic reactions are specific to a single organelle, others occur in more than one cellular compartment. Specific targeting of proteins to compartments inside of eukaryotic cells is mediated by defined sequence motifs. To achieve multiple targeting to different compartments cells use a variety of strategies. Here, we focus on mechanisms leading to dual targeting of peroxisomal proteins. In many instances, isoforms of peroxisomal proteins with distinct intracellular localization are encoded by separate genes. But also single genes can give rise to differentially localized proteins. Different isoforms can be generated by use of alternative transcriptional start sites, by differential splicing or ribosomal read-through of stop codons. In all these cases different peptide variants are produced, of which only one carries a peroxisomal targeting signal. Alternatively, peroxisomal proteins contain additional signals that compete for intracellular targeting. Dual localization of proteins residing in both the cytoplasm and in peroxisomes may also result from use of inefficient targeting signals. The recent observation that some bona fide cytoplasmic enzymes were also found in peroxisomes indicates that dual targeting of proteins to both the cytoplasm and the peroxisome might be more widespread. Although current knowledge of proteins exhibiting only partial peroxisomal targeting is far from being complete, we speculate that the metabolic capacity of peroxisomes might be larger than previously assumed.

  5. SENESCENCE-ASSOCIATED DECLINE IN HEPATIC PEROXISOMAL ENZYME ACTIVITIES CORRESPONDS WITH DIMINISHED LEVELS OF RETINOID X RECEPTOR ALPHA, BUT NOT PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA1

    EPA Science Inventory

    Abstract

    Aging is associated with alterations in hepatic peroxisomal metabolism and susceptibility to hepatocarcinogenecity produced by agonists of peroxisome proliferator-activated receptor alpha (PPARa). Mechanisms involved in these effects are not well understood. Howev...

  6. Developmental toxicity of perfluorononanoic acid is dependent on peroxisome proliferator activated receptor-alpha.

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is one of the predominant perfluoroalkyl acids in the environment and in tissues of humans and wildlife. PFNA strongly activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPARα) in vitro and negatively impacts development ...

  7. The roles of peroxisome proliferator-activated receptors in the metabolic syndrome.

    PubMed

    Mansour, Mahmoud

    2014-01-01

    The epidemic of obesity and its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X, is one of the most challenging health problems facing industrialized countries. The nuclear receptors, peroxisome proliferator-activated receptors (PPARs alpha (α), beta (β) also known as delta (δ), and gamma (γ)), have well-documented roles in lipid and glucose metabolism. Pharmacologically, PPARα is activated by fibrate hypolipidemic drugs, whereas PPARγ is activated by insulin sensitizers thiazolidinediones (TZDs). No marketed drug is yet available for PPARβ(δ). The identification of fibrates and TZDs as respective ligands for PPARα and PPARγ was a groundbreaking finding that sparked notable pharmaceutical interest in PPARs as potential drug targets for treatment of the metabolic syndrome. Limiting side effects associated with clinical use of TZDs have emerged in recent years. New and novel PPAR drugs with broad safety margins and therapeutic potentials for the metabolic syndrome are in development. These include partial, dual, or pan PPAR agonists; PPAR antagonists; and selective PPAR modulators. The objective of this chapter is to highlight the therapeutic benefits of targeting more than one PPAR subtype in the treatment of the metabolic syndrome. The pros and cons observed during clinical use of TZDs and the strategies and progress made in the production of new generations of safe and effective PPAR ligands are discussed. PMID:24373239

  8. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

    PubMed

    Cho, Nobuo; Momose, Yu

    2008-01-01

    An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes. PMID:19075761

  9. Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity

    PubMed Central

    Sáez, María E; Grilo, Antonio; Morón, Francisco J; Manzano, Luis; Martínez-Larrad, María T; González-Pérez, Antonio; Serrano-Hernando, Javier; Ruiz, Agustín; Ramírez-Lorca, Reposo; Serrano-Ríos, Manuel

    2008-01-01

    Context Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. Objective To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. Design Cross-sectional, genetic association study and gene-gene interaction analysis. Subjects The study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30) and 1228 non obese subjects. Results In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%. Conclusion Our results suggest that CAPN5 and PPARD gene products may also interact in vivo. PMID:18657264

  10. Peroxisome Proliferator-Activated Receptor Alpha (PPARa), Beta (PPARI3), and Gamma (PPARy) Expression in Human Fetal Tissues.

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study uses qPCR...

  11. Peroxisome Proliferator Activated Receptors Alpha, Beta, and Gamma mRNA and protein expression in human fetal tissues

    EPA Science Inventory

    Peroxisome proliferator-activated receptors (PPARs) regulate lipid and glucose homeostasis, are targets of pharmaceuticals, and are also activated by environmental contaminants. Almost nothing is known about expression of PPARs during human fetal development. This study examine...

  12. Fermented Ginseng Contains an Agonist of Peroxisome Proliferator Activated Receptors α and γ.

    PubMed

    Igami, Kentaro; Shimojo, Yosuke; Ito, Hisatomi; Miyazaki, Toshitsugu; Nakano, Fusako; Kashiwada, Yoshiki

    2016-09-01

    Peroxisome proliferator activated receptor (PPAR) is a nuclear receptor that is one of the transcription factors regulating lipid and glucose metabolism. Fermented ginseng (FG) is a ginseng fermented by Lactobacillus paracasei A221 containing minor ginsenosides and metabolites of fermentation. DNA microarray analysis of rat liver treated with FG indicated that FG affects on lipid metabolism are mediated by PPAR-α. To identify a PPAR-α agonist in FG, PPAR-α transcription reporter assay-guided fractionation was performed. The fraction obtained from the MeOH extract of FG, which showed potent transcription activity of PPAR-α, was fractionated by silica gel column chromatography into 16 subfractions, and further separation and crystallization gave compound 1 together with four known constituents of ginseng, including 20(R)- and 20(S)-protopanaxadiol, and 20(R)- and 20(S)-ginsenoside Rh1. The structure of compound 1 was identified as 10-hydroxy-octadecanoic acid by (1)H- and (13)C-NMR spectra and by EI-MS analysis of the methyl ester of 1. Compound 1 demonstrated much higher transcription activity of PPAR-α than the other isolated compounds. In addition, compound 1 also showed 5.5-fold higher transcription activity of PPAR-γ than vehicle at the dose of 20 μg/mL. In the present study, we identified 10-hydroxy-octadecanoic acid as a dual PPAR-α/γ agonist in FG. Our study suggested that metabolites of fermentation, in addition to ginsenosides, contribute to the health benefits of FG. PMID:27627700

  13. THE ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS IN CARCINOGENESIS AND CHEMOPREVENTION

    PubMed Central

    Peters, Jeffrey M.; Shah, Yatrik M.; Gonzalez, Frank J.

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a balanced review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists. PMID:22318237

  14. Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

    SciTech Connect

    Oyama, Takuji; Toyota, Kenji; Waku, Tsuyoshi; Hirakawa, Yuko; Nagasawa, Naoko; Kasuga, Jun-ichi; Hashimoto, Yuichi; Miyachi, Hiroyuki; Morikawa, Kosuke

    2009-08-01

    The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level. Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family, which is defined as transcriptional factors that are activated by the binding of ligands to their ligand-binding domains (LBDs). Although the three PPAR subtypes display different tissue distribution patterns and distinct pharmacological profiles, they all are essentially related to fatty-acid and glucose metabolism. Since the PPARs share similar three-dimensional structures within the LBDs, synthetic ligands which simultaneously activate two or all of the PPARs could be potent candidates in terms of drugs for the treatment of abnormal metabolic homeostasis. The structures of several PPAR LBDs were determined in complex with synthetic ligands, derivatives of 3-(4-alkoxyphenyl)propanoic acid, which exhibit unique agonistic activities. The PPARα and PPARγ LBDs were complexed with the same pan agonist, TIPP-703, which activates all three PPARs and their crystal structures were determined. The two LBD–ligand complex structures revealed how the pan agonist is adapted to the similar, but significantly different, ligand-binding pockets of the PPARs. The structures of the PPARδ LBD in complex with an α/δ-selective ligand, TIPP-401, and with a related δ-specific ligand, TIPP-204, were also determined. The comparison between the two PPARδ complexes revealed how each ligand exhibits either a ‘dual selective’ or ‘single specific’ binding mode.

  15. Modulation of Receptor Phosphorylation Contributes to Activation of Peroxisome Proliferator Activated Receptor α by Dehydroepiandrosterone and Other Peroxisome Proliferators

    PubMed Central

    Tamasi, Viola; Miller, Kristy K. Michael; Ripp, Sharon L.; Vila, Ermin; Geoghagen, Thomas E.; Prough, Russell A.

    2008-01-01

    Dehydroepiandrosterone (DHEA), a C19 human adrenal steroid, activates peroxisome proliferator-activated receptor α (PPARα) in vivo but does not ligand-activate PPARα in transient transfection experiments. We demonstrate that DHEA regulates PPARα action by altering both the levels and phosphorylation status of the receptor. Human hepatoma cells (HepG2) were transiently transfected with the expression plasmid encoding PPARα and a plasmid containing two copies of fatty acyl coenzyme oxidase (FACO) peroxisome-proliferator activated receptor responsive element consensus oligonucleotide in a luciferase reporter gene. Nafenopin treatment increased reporter gene activity in this system, whereas DHEA treatment did not. Okadaic acid significantly decreased nafenopin-induced reporter activity in a concentration-dependent manner. Okadaic acid treatment of primary rat hepatocytes decreased both DHEA- and nafenopin-induced FACO activity in primary rat hepatocytes. DHEA induced both PPARα mRNA and protein levels, as well as PP2A message in primary rat hepatocytes. Western blot analysis showed that the serines at positions 12 and 21 were rapidly dephosphorylated upon treatment with DHEA and nafenopin. Results using specific protein phosphatase inhibitors suggested that protein phosphatase 2A (PP2A) is responsible for DHEA action, and protein phosphatase 1 might be involved in nafenopin induction. Mutation of serines at position 6, 12, and 21 to an uncharged alanine residue significantly increased transcriptional activity, whereas mutation to negative charged aspartate residues (mimicking receptor phosphorylation) decreased transcriptional activity. DHEA action involves induction of PPARα mRNA and protein levels as well as increased PPARα transcriptional activity through decreasing receptor phosphorylation at serines in the AF1 region. PMID:18079279

  16. Mode of action framework analysis for receptor-mediated toxicity: the Peroxisome Proliferator-Activated Receptor alpha (PPARα) as a case study

    EPA Science Inventory

    Therapeutic hypolipidemic agents and industrial chemicals that cause peroxisome proliferation and induce liver tumors in rodents activate the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα). Research has elucidated the cellular and molecular events by w...

  17. A peroxisome proliferator-activated receptor-gamma agonist and other constituents from Chromolaena odorata.

    PubMed

    Dat, Nguyen Tien; Lee, Kyeong; Hong, Young-Soo; Kim, Young Ho; Minh, Chau Van; Lee, Jung Joon

    2009-06-01

    Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid and glucose metabolism and have become important therapeutic targets for various diseases. The phytochemical investigation of the chloroform-soluble extract of Chromolaena odorata led to the isolation of a PPAR-gamma agonist, (9 S,13 R)-12-oxo-phytodienoic acid (1), together with 12 other compounds. The structures of chromomoric acid G (2), a new dehydrogenated derivative of 1, and chromolanone (3) were elucidated based on spectroscopic methods. Compound 1 showed a significant effect on PPAR-gamma activation in comparison with rosiglitazone. However, compound 2 was inactive, suggesting that the dehydrogenation of the prostaglandin-like structure in 1 abrogates its PPAR-gamma agonistic activity.

  18. Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology.

    PubMed

    Liu, Li-Li; Xian, Hua; Cao, Jing-Chen; Zhang, Chong; Zhang, Yong-Hui; Chen, Miao-Miao; Qian, Yi; Jiang, Ming

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARγ acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγ protein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARγ signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.

  19. Wakayama Symposium: Peroxisome Proliferator-Activated Receptor-gamma (PPARγ) and Meibomian Gland Dysfunction

    PubMed Central

    Jester, James V.; Brown, Donald J.

    2012-01-01

    Recently we have shown that mouse and human meibomian glands undergo specific age-related changes, including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPARγ) localization from cytoplasmic-vesicular/nuclear in young mice and humans to nuclear in old mice and humans. Since PPARγ is a lipid-sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPARγ may be involved in modulating meibomian gland differentiation during aging. Based on these findings, we propose that aging of the meibomian gland results in downregulation of PPARγ, leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory meibomian gland dysfunction. PMID:23084144

  20. Peroxisome Proliferator-Activated Receptor-γ Is Critical to Cardiac Fibrosis

    PubMed Central

    Liu, Huang-Jun; Liao, Hai-Han; Yang, Zheng; Tang, Qi-Zhu

    2016-01-01

    Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγ agonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγ in various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγ agonists for the clinical management of CVD. PMID:27293418

  1. The Role of Peroxisome Proliferator-Activated Receptors in Pulmonary Vascular Disease

    PubMed Central

    Nisbet, Rachel E.; Sutliff, Roy L.; Hart, C. Michael

    2007-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily that regulate diverse physiological processes ranging from lipogenesis to inflammation. Recent evidence has established potential roles of PPARs in both systemic and pulmonary vascular disease and function. Existing treatment strategies for pulmonary hypertension, the most common manifestation of pulmonary vascular disease, are limited by an incomplete understanding of the underlying disease pathogenesis and lack of efficacy indicating an urgent need for new approaches to treat this disorder. Derangements in pulmonary endothelial-derived mediators and endothelial dysfunction have been shown to play a pivotal role in pulmonary hypertension pathogenesis. Therefore, the following review will focus on selected mediators implicated in pulmonary vascular dysfunction and evidence that PPARs, in particular PPARγ, participate in their regulation and may provide a potential novel therapeutic target for the treatment of pulmonary hypertension. PMID:17710111

  2. Wakayama Symposium: Peroxisome proliferator-activated receptor-gamma (PPARγ) and meibomian gland dysfunction.

    PubMed

    Jester, James V; Brown, Donald J

    2012-10-01

    Recently we have shown that mouse and human meibomian glands undergo specific age-related changes, including decreased acinar cell proliferation, acinar atrophy, and altered peroxisome proliferator-activated receptor gamma (PPARγ) localization from cytoplasmic-vesicular/nuclear in young mice and humans to nuclear in old mice and humans. Since PPARγ is a lipid-sensitive, nuclear receptor implicated in regulating adipocyte and sebocyte differentiation and lipogenesis, our findings suggest that PPARγ may be involved in modulating meibomian gland differentiation during aging. Based on these findings, we propose that aging of the meibomian gland results in downregulation of PPARγ, leading to decreased meibocyte differentiation and lipid synthesis, gland atrophy, and a hyposecretory meibomian gland dysfunction.

  3. Peroxisome proliferator-activated receptors as molecular targets in relation to obesity and type 2 diabetes.

    PubMed

    Seda, Ondørej; Sedová, Lucie

    2007-06-01

    The three isotypes of peroxisome proliferator-activated receptors (PPARs) are currently perceived as major regulatory nodes (or hubs) of metabolic pathway networks, linking most prevalent diseases including Type 2 diabetes, obesity, dyslipidemia and atherosclerosis. The integrative functions of PPARs are also reflected in their ecogenetic profile, when the variants underlying pharmacogenetic interactions were also shown to modulate the effect of lifestyle factors. Despite their extensive clinical use, there are many outstanding issues, especially concerning their safety. Critical pharmacogenomic assessment is warranted for the new potent ligands of multiple PPAR isoforms as many have displayed serious side-effects in a limited number of treated subjects. Nevertheless, the advent of genomic, transcriptomic and system biology-level approaches, integrating knowledge from model systems and human biology, should greatly facilitate the transition to individualized PPAR-based therapies.

  4. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors

    PubMed Central

    Xu, H. Eric; Lambert, Millard H.; Montana, Valerie G.; Plunket, Kelli D.; Moore, Linda B.; Collins, Jon L.; Oplinger, Jeffery A.; Kliewer, Steven A.; Gampe, Robert T.; McKee, David D.; Moore, John T.; Willson, Timothy M.

    2001-01-01

    The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of glucose, lipid, and cholesterol metabolism. We report the x-ray crystal structure of the ligand binding domain of PPARα (NR1C1) as a complex with the agonist ligand GW409544 and a coactivator motif from the steroid receptor coactivator 1. Through comparison of the crystal structures of the ligand binding domains of the three human PPARs, we have identified molecular determinants of subtype selectivity. A single amino acid, which is tyrosine in PPARα and histidine in PPARγ, imparts subtype selectivity for both thiazolidinedione and nonthiazolidinedione ligands. The availability of high-resolution cocrystal structures of the three PPAR subtypes will aid the design of drugs for the treatments of metabolic and cardiovascular diseases. PMID:11698662

  5. Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions

    PubMed Central

    Lee, Wang-Soo; Kim, Jaetaek

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs. PMID:26587015

  6. Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases

    PubMed Central

    Zhang, Su; Gu, Hongwei; Hu, Nan

    2015-01-01

    Peroxisome proliferator-activated receptor γ (PPAR γ), a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases. PMID:26146566

  7. Targeting the Peroxisome Proliferator-Activated Receptor-γ to Counter the Inflammatory Milieu in Obesity.

    PubMed

    Corzo, Cesar; Griffin, Patrick R

    2013-12-01

    Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator-activated receptor-γ have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here.

  8. Targeting the Peroxisome Proliferator-Activated Receptor-γ to Counter the Inflammatory Milieu in Obesity

    PubMed Central

    Corzo, Cesar

    2013-01-01

    Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator-activated receptor-γ have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here. PMID:24404510

  9. Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the 'future' in dermatology therapeutics?

    PubMed

    Gupta, Mrinal; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu

    2015-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and comprise three different isoforms namely PPARα, PPARγ, and PPARβ/δ with PPARβ/δ being the predominant subtype in human keratinocytes. After binding with specific ligands, PPARs regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorogenesis. PPARs also modulate a wide variety of skin functions including keratinocyte proliferation, epidermal barrier formation, wound healing, melanocyte proliferation, and sebum production. Recent studies have shown the importance of PPARs in the pathogenesis of many dermatological disorders. Clinical trials have suggested possible role of PPAR agonists in the management of various dermatoses ranging from acne vulgaris, psoriasis, hirsutism, and lipodystrophy to cutaneous malignancies including melanoma. This article is intended to be a primer for dermatologists in their understanding of clinical relevance of PPARs and PPAR agonists in dermatology therapeutics.

  10. Peroxisome proliferator-activated receptor-alpha expression in rat liver during postnatal development.

    PubMed

    Panadero, M; Herrera, E; Bocos, C

    2000-08-01

    The expression of the peroxisome proliferator-activated receptor-alpha (PPARalpha) as well as of some related genes was studied in rat liver at different stages of development (from 19-day-old fetuses to 1 month-old rats). The level of PPARalpha mRNA appeared higher in neonates than in fetuses or 1 month-old rats. Whereas the pattern for phosphoenolpyruvate carboxykinase (PEPCK) mRNA level was similar to that of PPARalpha, the mRNA level of both acyl-CoA oxidase (ACO) and apolipoprotein CIII (apo CIII) showed diverse profiles. Western blotting analysis also revealed an increased level of PPARalpha protein in liver of suckling rats. Similarities of mRNA PEPCK and PPARalpha expression indicate a common control mechanism, where both nutritional and hormonal factors may be involved. PMID:11018288

  11. Ligands and Regulatory Modes of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Avians.

    PubMed

    Navidshad, Bahman; Royan, M

    2015-01-01

    Nutrient and gene interaction is an important aspect of poultry metabolism that determines performance capacity. New technological tools in biochemistry and biotechnology make it possible to explore the molecular base of phenotypic characteristics of poultry production. Fats act as energy deposits in the poultry body and are an essential constituent of animal cell membranes. From a functional standpoint, it has been suggested that ingested lipids change liver fatty acid synthesis and other lipogenic enzymes by regulating mRNA synthesis. Nuclear hormone receptors are ligand-activated transcription factors that control several genes involved in lipid metabolism. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors. Three separate PPAR genes have been identified; they are known as α, δ, and γ. The most important metabolic effect of PPARγ in chicken is its task in adipogenesis. Reviewing the ligands of chicken PPARγ gene can be useful to a better understanding of PPARγ regulatory functions.

  12. Mechanisms of peroxisome proliferator activated receptor γ regulation by non-steroidal anti-inflammatory drugs

    PubMed Central

    Puhl, Ana C.; Milton, Flora A.; Cvoro, Aleksandra; Sieglaff, Douglas H.; Campos, Jéssica C.L.; Bernardes, Amanda; Filgueira, Carly S.; Lindemann, Jan Lammel; Deng, Tuo; Neves, Francisco A.R.; Polikarpov, Igor; Webb, Paul

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) display anti-inflammatory, antipyretic and analgesic properties by inhibiting cyclooxygenases and blocking prostaglandin production. Previous studies, however, suggested that some NSAIDs also modulate peroxisome proliferator activated receptors (PPARs), raising the possibility that such off target effects contribute to the spectrum of clinically relevant NSAID actions. In this study, we set out to understand how peroxisome proliferator activated receptor-γ (PPARγ/PPARG) interacts with NSAIDs using X-ray crystallography and to relate ligand binding modes to effects on receptor activity. We find that several NSAIDs (sulindac sulfide, diclofenac, indomethacin and ibuprofen) bind PPARγ and modulate PPARγ activity at pharmacologically relevant concentrations. Diclofenac acts as a partial agonist and binds to the PPARγ ligand binding pocket (LBP) in typical partial agonist mode, near the β-sheets and helix 3. By contrast, two copies of indomethacin and sulindac sulfide bind the LBP and, in aggregate, these ligands engage in LBP contacts that resemble agonists. Accordingly, both compounds, and ibuprofen, act as strong partial agonists. Assessment of NSAID activities in PPARγ-dependent 3T3-L1 cells reveals that NSAIDs display adipogenic activities and exclusively regulate PPARγ-dependent target genes in a manner that is consistent with their observed binding modes. Further, PPARγ knockdown eliminates indomethacin activities at selected endogenous genes, confirming receptor-dependence of observed effects. We propose that it is important to consider how individual NSAIDs interact with PPARγ to understand their activities, and that it will be interesting to determine whether high dose NSAID therapies result in PPAR activation. PMID:26445566

  13. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome

    PubMed Central

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-01-01

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu162Val and Val227Ala of PPARα, +294T > C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies. PMID:25987964

  14. Peroxisome proliferator-activated receptor-α activation and excess energy burning in hepatocarcinogenesis.

    PubMed

    Misra, Parimal; Reddy, Janardan K

    2014-03-01

    Peroxisome proliferator-activated receptor-α (PPARα) modulates the activities of all three interlinked hepatic fatty acid oxidation systems, namely mitochondrial and peroxisomal β-oxidation and microsomal ω-oxidation pathways. Hyperactivation of PPARα, by both exogenous and endogenous activators up-regulates hepatic fatty acid oxidation resulting in excess energy burning in liver contributing to the development of liver cancer in rodents. Sustained PPARα signaling disproportionately increases H2O2-generating fatty acid metabolizing enzymes as compared to H2O2-degrading enzymes in liver leading to enhanced generation of DNA damaging reactive oxygen species, progressive endoplasmic reticulum stress and inflammation. These alterations also contribute to increased liver cell proliferation with changes in apoptosis. Thus, reactive oxygen species, oxidative stress and hepatocellular proliferation are likely the main contributing factors in the pathogenesis of hepatocarcinogenesis, mediated by sustained PPARα activation-related energy burning in liver. Furthermore, the transcriptional co-activator Med1, a key subunit of the Mediator complex, is essential for PPARα signaling in that both PPARα-null and Med1-null hepatocytes are unresponsive to PPARα activators and fail to give rise to liver tumors when chronically exposed to PPARα activators.

  15. Developmental Effects of Perfluorononanoic acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-alpha

    EPA Science Inventory

    Perfluorononanoic acid (PFNA) is one ofthe perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated recept...

  16. Targeting components of the stress system as potential therapies for the metabolic syndrome: the peroxisome-proliferator-activated receptors.

    PubMed

    Yumuk, Volkan D

    2006-11-01

    The three peroxisome-proliferator-activated receptor (PPAR) subtypes PPAR-alpha, PPAR-gamma, and PPAR-delta are ligand-activated transcription factors of the nuclear receptor family. PPARs form obligate heterodimers with the retinoid X receptor, which bind to peroxisome-proliferator-response elements (PPREs). PPAR-alpha is expressed mainly in liver, brown fat, kidney, heart, and skeletal muscle; PPAR-gamma in intestine and adipose tissue; PPAR-alpha and PPAR-gamma are both expressed in vascular endothelium, smooth muscle cells, macrophages, and foam cells; PPAR-delta in skeletal muscle, human embryonic kidney, intestine, heart, adipose tissue, developing brain, and keratinocytes. Intense interest in the development of drugs with new mechanisms of action for the metabolic syndrome has focused attention on nuclear receptors, such as PPARs that function as regulators of energy homeostasis. Agonists of PPAR-alpha and PPAR-gamma are currently used to treat diabetic dyslipidemia and type 2 diabetes. Dual PPAR-alpha/gamma agonists and PPAR-alpha/gamma/delta pan-agonists are under investigation for treatment of cardiovascular disease and the metabolic syndrome. Selective PPAR modulators (SPPARMs) are PPAR ligands that possess desirable efficacy and improved tolerance. Efforts are being made to identify novel partial agonists or antagonists for PPAR-gamma in order to combine their antidiabetic and antiobesity effects. Glucocorticoids are major mediators of the stress response and could be the link between stress and PPAR activator signaling and thus may affect the downstream metabolic pathways involved in fuel homeostasis. PMID:17148746

  17. Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage.

    PubMed

    Garcia-Vallvé, Santiago; Guasch, Laura; Tomas-Hernández, Sarah; del Bas, Josep Maria; Ollendorff, Vincent; Arola, Lluís; Pujadas, Gerard; Mulero, Miquel

    2015-07-23

    Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs. PMID:25734377

  18. Berberine is a potent agonist of peroxisome proliferator activated receptor alpha.

    PubMed

    Yu, Huarong; Li, Changqing; Yang, Junqing; Zhang, Tao; Zhou, Qixin

    2016-01-01

    Although berberine has hypolipidemic effects with a high affinity to nuclear proteins, the underlying molecular mechanism for this effect remains unclear. Here, we determine whether berberine is an agonist of peroxisome proliferator-activated receptor alpha (PPARalpha), with a lipid-lowering effect. The cell-based reporter gene analysis showed that berberine selectively activates PPARalpha (EC50 =0.58 mM, Emax =102.4). The radioligand binding assay shows that berberine binds directly to the ligand-binding domain of PPARalpha (Ki=0.73 mM) with similar affinity to fenofibrate. The mRNA and protein levels of CPT-Ialpha gene from HepG2 cells and hyperlipidemic rat liver are remarkably up-regulated by berberine, and this effect can be blocked by MK886, a non-competitive antagonist of PPARalpha. A comparison assay in which berberine and fenofibrate were used to treat hyperlipidaemic rats for three months shows that these drugs produce similar lipid-lowering effects, except that berberine increases high-density lipoprotein cholesterol more effectively than fenofibrate. These findings provide the first evidence that berberine is a potent agonist of PPARalpha and seems to be superior to fenofibrate for treating hyperlipidemia. PMID:27100490

  19. The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development.

    PubMed

    Lendvai, Ágnes; Deutsch, Manuel J; Plösch, Torsten; Ensenauer, Regina

    2016-05-15

    The placental metabolism can adapt to the environment throughout pregnancy to both the demands of the fetus and the signals from the mother. Such adaption processes include epigenetic mechanisms, which alter gene expression and may influence the offspring's health. These mechanisms are linked to the diversity of prenatal environmental exposures, including maternal under- or overnutrition or gestational diabetes. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that contribute to the developmental plasticity of the placenta by regulating lipid and glucose metabolism pathways, including lipogenesis, steroidogenesis, glucose transporters, and placental signaling pathways, thus representing a link between energy metabolism and reproduction. Among the PPAR isoforms, PPARγ appears to be the main modulator of mammalian placentation. Certain fatty acids and lipid-derived moieties are the natural activating PPAR ligands. By controlling the amounts of maternal nutrients that go across to the fetus, the PPARs play an important regulatory role in placenta metabolism, thereby adapting to the maternal nutritional status. As demonstrated in animal studies, maternal nutrition during gestation can exert long-term influences on the PPAR methylation pattern in offspring organs. This review underlines the current state of knowledge on the relationship between environmental factors and the epigenetic regulation of the PPARs in placenta metabolism and offspring development. PMID:26860983

  20. A role for Peroxisome Proliferator-Activated Receptor Beta in T cell development

    PubMed Central

    Mothe-Satney, Isabelle; Murdaca, Joseph; Sibille, Brigitte; Rousseau, Anne-Sophie; Squillace, Raphaëlle; Le Menn, Gwenaëlle; Rekima, Akila; Larbret, Frederic; Pelé, Juline; Verhasselt, Valérie; Grimaldi, Paul A.; Neels, Jaap G.

    2016-01-01

    Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4−CD8− double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells. PMID:27680392

  1. Three peroxisome proliferator-activated receptor isotypes from each of two species of marine fish.

    PubMed

    Leaver, Michael J; Boukouvala, Evridiki; Antonopoulou, Efthimia; Diez, Amalia; Favre-Krey, Laurence; Ezaz, M Tariq; Bautista, José M; Tocher, Douglas R; Krey, Grigorios

    2005-07-01

    The cloning and characterization of cDNAs and genes encoding three peroxisome proliferator-activated receptor (PPAR) isotypes from two species of marine fish, the plaice (Pleuronectes platessa) and the gilthead sea bream (Sparus aurata), are reported for the first time. Although differences in the genomic organization of the fish PPAR genes compared with their mammalian counterparts are evident, sequence alignments and phylogenetic comparisons show the fish genes to be homologs of mammalian PPARalpha, PPARbeta/delta, and PPARgamma. Like their mammalian homologs, fish PPARs bind to a variety of natural PPAR response elements (PPREs) present in the promoters of mammalian or piscine genes. In contrast, the mRNA expression pattern of PPARs in the two fish species differs from that observed in other vertebrates. Thus, PPARgamma is expressed more widely in fish tissues than in mammals, whereas PPARalpha and beta are expressed similarly in profile to mammals. Furthermore, nutritional status strongly influences the expression of all three PPAR isotypes in liver, whereas it has no effect on PPAR expression in intestinal and adipose tissues. Fish PPARalpha and beta exhibit an activation profile similar to that of the mammalian PPAR in response to a variety of activators/ligands, whereas PPARgamma is not activated by mammalian PPARgamma-specific ligands. Amino acid residues shown to be critical for ligand binding in mammalian PPARs are not conserved in fish PPARgamma and therefore, together with the distinct tissue expression profile of this receptor, suggest potential differences in the function of PPARgamma in fish compared with mammals.

  2. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma.

    PubMed Central

    De Vos, P; Lefebvre, A M; Miller, S G; Guerre-Millo, M; Wong, K; Saladin, R; Hamann, L G; Staels, B; Briggs, M R; Auwerx, J

    1996-01-01

    The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter. PMID:8770873

  3. Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar.

    PubMed

    Liu, Xu-Yuan; Wang, Run-Ling; Xu, Wei-Ren; Tang, Li-Da; Wang, Shu-Qing; Chou, Kuo-Chen

    2011-10-01

    PPAR (peroxisome proliferator-activated receptor) pan agonists play a critical role in treating metabolic diseases, especially the Type-2 diabetes mellitus (T2DM). GlaxoSmithKline's sodelglitazar (GW677954) is one of the potent PPAR pan agonists, which is currently being investigated in Phase II clinical trials for the treatment of T2DM and its complications. The present study was aimed at investigation into the effect of sodelglitazar at the binding pockets of PPARs. The Schrodinger Suite program (2009) was used for the molecular docking, while the GROMACS program used for the molecular dynamics (MD) simulations. The results thus obtained showed that sodelglitazar being docked well in the active site of PPARs. It was revealed by the MD simulations that the structures of the receptors remained quite stable during the simulations and that the important AF-2 helix showed less flexibility after binding with sodelglitazar. Also, it was observed that sodelglitazar could periodically form hydrogen bonds with the AF-2 helix of PPARs to stabilize the AF-2 helix in an active conformation. Our findings have confirmed that GlaxoSmithKline's sodelglitazar can activate the PPARs, which is quite consistent with the previous biological studies. PMID:21592078

  4. Peroxisome proliferator-activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma.

    PubMed

    Nickkho-Amiry, Mahshid; McVey, Rhona; Holland, Cathrine

    2012-03-01

    Peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR) are implicated in the development of several obesity-related cancers. Little is known of either the expression or function of PPARs and RXRs in endometrial cancer although this increasingly common disease is highly associated with both obesity and insulin resistance. We investigated the expression of PPAR and RXR subtypes in human endometrial cancers and normal endometrium with immunoblotting and immunohistochemistry and subsequently showed PPAR/RXR binding preferences by coimmunoprecipitation. To determine the functions of PPARs within the endometrium, we investigated proliferation, apoptosis, PTEN expression, and secretion of vascular endothelial growth factor (VEGF) in endometrial cell lines after reducing the expression of PPARα and PPARγ with antisense RNA. The functional effects of PPAR ligands were also investigated in vitro. We identified differential expression of PPAR and RXR subtypes in endometrial cancers and discovered that PPARγ expression correlated with expression of PTEN. PPARα activation influences endometrial cell growth and VEGF secretion. PPARγ activation reduces proliferation of endometrial cells via regulation of PTEN and appears to reduce VEGF secretion. We conclude that the PPAR/RXR pathway contribute to endometrial carcinogenesis by control of PTEN expression and modulation of VEGF secretion. We propose that PPAR ligands should be considered for clinical investigation in early phase studies of women with endometrial cancer.

  5. Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Mandard, Stéphane; Patsouris, David

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARα and PPARβ/δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits. PMID:23577023

  6. Peroxisome proliferator-activated receptors in the regulation of female reproductive functions.

    PubMed

    Bogacka, Iwona; Kurzynska, Aleksandra; Bogacki, Marek; Chojnowska, Katarzyna

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) belong to a ligand-dependent nuclear receptor family. In the past decade, numerous studies have revealed the presence and significance of PPARs in the reproductive system. PPARs are expressed at different levels of hypothalamic-pituitary-gonadal (HPG) axis. They are also present in the uterus as well as in the placenta and embryonic tissues of different species. PPARs significance has been reported during the estrous/menstrual cycle and pregnancy with the gamma isoform studied most frequently. Several studies indicate that PPARs regulate proliferation of ovarian cells, tissue remodeling and steroidogenesis. In the endometrium, PPARs are engaged in the regulation of prostaglandins, steroids and cytokines synthesis. The role of PPARs in the trophoblast differentiation, maturation and invasion as well as in the embryo development has also been demonstrated. In this review, we summarize current findings concerning the role of PPARs in the regulation of reproductive functions at different levels of the HPG axis during various physiological statuses of females. In addition, the role of PPARs in the modulation of uterine functions as well as the placenta and embryo development has also been discussed.

  7. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer

    PubMed Central

    Polvani, Simone; Tarocchi, Mirko; Tempesti, Sara; Bencini, Lapo; Galli, Andrea

    2016-01-01

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients. PMID:26937133

  8. The biology of the peroxisome proliferator-activated receptor system in the female reproductive tract.

    PubMed

    Vélez, Leandro Martín; Abruzzese, Giselle Adriana; Motta, Alicia Beatriz

    2013-01-01

    Fuel sensors such as glucose, insulin or leptin, are known to be directly involved in the regulation of fertility at each level of the hypothalamic-pituitary-gonadal axis. The discovery of the peroxisome proliferator-activated receptor (PPAR) family of transcription factors has revealed the link between lipid/glucose availability and long-term metabolic adaptation. By binding to specific regions of DNA in heterodimers with the retinoid X receptors (RXRs), the members of the PPAR family (α, β/δ, γ) are able to regulate the gene expressions of several key regulators of energy homeostasis including several glucose regulators (glucose transporters, insulin receptor, substrate insulin receptor, etc), and also metabolic and endocrine pathways like lipogenesis, steroidogenesis, ovulation, oocyte maturation, maintenance of the corpus luteum, nitric oxide system, several proteases and plasminogen activator among others. All the three PPAR isoforms are expressed in different tissues of the female reproductive tract and regulate gametogenesis, ovulation, corpus luteum regression and the implantation process among others. The present review discusses the mechanisms involved in PPAR activation focusing on endogenous and synthetic ligands of PPAR not only in physiological but also in pathological conditions (such as polycystic ovary syndrome, pathologies of implantation process, chronic anovulation, etc).

  9. Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma.

    PubMed

    De Vos, P; Lefebvre, A M; Miller, S G; Guerre-Millo, M; Wong, K; Saladin, R; Hamann, L G; Staels, B; Briggs, M R; Auwerx, J

    1996-08-15

    The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter.

  10. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    PubMed

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

  11. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor Alpha Selective

    SciTech Connect

    Li, J.; Kennedy, L; Shi, Y; Tao, S; Ye, X; Chen, S; Wang, Y; Hernandez, A; Wang, W; et al.

    2010-01-01

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and {approx}410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

  12. Mitofusin 2 decreases intracellular lipids in macrophages by regulating peroxisome proliferator-activated receptor-γ

    SciTech Connect

    Liu, Chun; Ge, Beihai; He, Chao; Zhang, Yi; Liu, Xiaowen; Liu, Kejian; Qian, Cuiping; Zhang, Yu; Peng, Wenzhong; Guo, Xiaomei

    2014-07-18

    Highlights: • Mfn2 decreases cellular lipid accumulation by activating cholesterol transporters. • PPARγ is involved in the Mfn2-mediated increase of cholesterol transporter expressions. • Inactivation of ERK1/2 and p38 is involved in Mfn2-induced PPARγ expression. - Abstract: Mitofusin 2 (Mfn2) inhibits atherosclerotic plaque formation, but the underlying mechanism remains elusive. This study aims to reveal how Mfn2 functions in the atherosclerosis. Mfn2 expression was found to be significantly reduced in arterial atherosclerotic lesions of both mice and human compared with healthy counterparts. Here, we observed that Mfn2 increased cellular cholesterol transporter expression in macrophages by upregulating peroxisome proliferator-activated receptor-γ, an effect achieved at least partially by inhibiting extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs) pathway. These findings provide insights into potential mechanisms of Mfn2-mediated alterations in cholesterol transporter expression, which may have significant implications for the treatment of atherosclerotic heart disease.

  13. Liver X Receptor β and Peroxisome Proliferator-Activated Receptor δ regulate cholesterol transport in cholangiocytes

    PubMed Central

    Xia, Xuefeng; Jung, Dongju; Webb, Paul; Zhang, Aijun; Zhang, Bin; Li, Lifei; Ayers, Stephen D.; Gabbi, Chiara; Ueno, Yoshiyuki; Gustafsson, Jan-Åke; Alpini, Gianfranco; Moore, David D.; LeSage, Gene D.

    2012-01-01

    Nuclear receptors (NRs) play crucial roles in regulation of hepatic cholesterol synthesis, metabolism and conversion to bile acids, but their actions in cholangiocytes have not been examined. In this study, we investigated the roles of NRs in cholangiocyte physiology and cholesterol metabolism and flux. We examined the expression of NRs and other genes involved in cholesterol homeostasis in freshly isolated and cultured rodent cholangiocytes and found that these cells express a specific subset of NRs which includes Liver X Receptor β (LXRβ) and Peroxisome Proliferator-Activated Receptor δ (PPARδ). Activation of LXRβ and/or PPARδ in cholangiocytes induces ATP-binding cassette cholesterol transporter A1 (ABCA1) and increases cholesterol export at the basolateral compartment in polarized cultured cholangiocytes. In addition, PPARδ induces Niemann Pick C1 Like L1 (NPC1L1), which imports cholesterol into cholangiocytes and is expressed on the apical cholangiocyte membrane, via specific interaction with a PPRE within the NPC1L1 promoter. Based on these studies, we propose that (i) LXRβ and PPARδ coordinate NPC1L1/ABCA1 dependent vectorial cholesterol flux from bile through cholangiocytes and (ii) manipulation of these processes may influence bile composition with important applications in cholestatic liver disease and gallstone disease, serious health concerns for humans. PMID:22729460

  14. Emerging role of the peroxisome proliferator-activated receptor-gamma in hepatocellular carcinoma

    PubMed Central

    Hsu, Hui-Tzu; Chi, Chin-Wen

    2014-01-01

    Hepatocellular carcinoma (HCC) is the major leading cause of cancer death worldwide. Hepatitis B virus, hepatitis C virus, alcohol consumption, non-alcoholic fatty liver disease, and diabetes are the major risks for developing HCC. Until now, recurrence and metastasis are the major cause of death in HCC patients. Therefore, identification of new effective molecular targets is an urgent need for treatment of HCC. Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor which could be activated by PPARγ agonists such as thiazolidinediones, and natural PPARγ ligand (such as 15-deoxy-Δ12,14-prostaglandin J2, 15d-PGJ2). Increasing in vitro and in vivo evidence has demonstrated that PPARγ agonists exhibit an inhibitory role on tumor cell growth, migration, and invasion, suggesting that PPARγ activation may play an important role in the regulation of growth of HCC. It has been reported that PPARγ activation by thiazolidinediones or overexpression of PPARγ by virus-mediated gene transfer has shown growth inhibitory effects in hepatoma cells, but the expression level of PPARγ in HCC tissues still remains conflicting. Notably, a novel PPARγ agonist, honokiol, has recently been found to activate the PPARγ/RXR heterodimer, and has also exhibited significant anti-cancer effects in hepatoma cells. In the present review, we summarized studies on the role and the molecular regulation of PPARγ in HCC development in vitro and in vivo. PPARγ has the potential to be a therapeutic target for future treatment of HCC. PMID:27508182

  15. Liver X Receptor and Peroxisome Proliferator-Activated Receptor Agonist from Cornus alternifolia

    PubMed Central

    He, Yang-Qing; Ma, Guo-Yi; Peng, Jiang-nan; Ma, Zhan-Ying; Hamann, Mark T.

    2012-01-01

    Background Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptors superfamily and are transcription factors activated by specific ligands. Liver X receptors (LXR) belong to the nuclear hormone receptors and have been shown to play an important role in cholesterol homeostasis. From the previous screening of several medicinal plants for potential partial PPARγ agonists, the extracts of Cornus alternifolia were found to exhibit promising bioactivity. In this paper, we report the isolation and structural elucidation of four new compounds and their potential as ligands for PPAR. Methods The new compounds were extracted from the leaves of Cornus alternifolia and fractionated by high-performance liquid chromatography. Their structures were elucidated on the basis of spectroscopic evidence and analysis of their hydrolysis products. Results Three new iridoid glycosides including an iridolactone, alternosides A-C (1–3), a new megastigmane glycoside, cornalternoside (4) and 10 known compounds, were obtained from the leaves of Cornus alternifolia. Kaempferol-3-O-β-glucopyranoside (5) exhibited potent agonistic activities for PPARα, PPARγ and LXR with EC50 values of 0.62, 3.0 and 1.8 μ M, respectively. Conclusions We isolated four new and ten known compounds from Cornus alternifolia, and one known compound showed agonistic activities for PPARα, PPARγ and LXR. General significance Compound 1 is the first example of a naturally occurring iridoid glycoside containing a β-glucopyranoside moiety at C-6. PMID:22353334

  16. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

    PubMed Central

    Lee, Hyun Jung; Yeon, Jong Eun; Ko, Eun Jung; Yoon, Eileen L; Suh, Sang Jun; Kang, Keunhee; Kim, Hae Rim; Kang, Seoung Hee; Yoo, Yang Jae; Je, Jihye; Lee, Beom Jae; Kim, Ji Hoon; Seo, Yeon Seok; Yim, Hyung Joon; Byun, Kwan Soo

    2015-01-01

    AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models. METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW. RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α. CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD. PMID:26668503

  17. Hepatic triacylglycerol hydrolysis regulates peroxisome proliferator-activated receptor alpha activity.

    PubMed

    Sapiro, Jessica M; Mashek, Mara T; Greenberg, Andrew S; Mashek, Douglas G

    2009-08-01

    Recent evidence suggests that fatty acids generated from intracellular triacylglycerol (TAG) hydrolysis may have important roles in intracellular signaling. This study was conducted to determine if fatty acids liberated from TAG hydrolysis regulate peroxisome proliferator-activated receptor alpha (PPARalpha). Primary rat hepatocyte cultures were treated with adenoviruses overexpressing adipose differentiation-related protein (ADRP) or adipose triacylglycerol lipase (ATGL) or treated with short interfering RNA (siRNA) targeted against ADRP. Subsequent effects on TAG metabolism and PPARalpha activity and target gene expression were determined. Overexpressing ADRP attenuated TAG hydrolysis, whereas siRNA-mediated knockdown of ADRP or ATGL overexpression resulted in enhanced TAG hydrolysis. Results from PPARalpha reporter activity assays demonstrated that decreasing TAG hydrolysis by ADRP overexpression resulted in a 35-60% reduction in reporter activity under basal conditions or in the presence of fatty acids. As expected, PPARalpha target genes were also decreased in response to ADRP overexpression. However, the PPARalpha ligand, WY-14643, was able to restore PPARalpha activity following ADRP overexpression. Despite its effects on PPARalpha, overexpressing ADRP did not affect PPARgamma activity. Enhancing TAG hydrolysis through ADRP knockdown or ATGL overexpression increased PPARalpha activity. These results indicate that TAG hydrolysis and the consequential release of fatty acids regulate PPARalpha activity.

  18. Engineering and optimization of an allosteric biosensor protein for peroxisome proliferator-activated receptor γ ligands.

    PubMed

    Li, Jingjing; Gierach, Izabela; Gillies, Alison R; Warden, Charles D; Wood, David W

    2011-11-15

    The peroxisome proliferator-activated receptor gamma (PPARγ or PPARG) belongs to the nuclear receptor superfamily, and is a potential drug target for a variety of diseases. In this work, we constructed a series of bacterial biosensors for the identification of functional PPARγ ligands. These sensors entail modified Escherichia coli cells carrying a four-domain fusion protein, comprised of the PPARγ ligand binding domain (LBD), an engineered mini-intein domain, the E. coli maltose binding protein (MBD), and a thymidylate synthase (TS) reporter enzyme. E. coli cells expressing this protein exhibit hormone ligand-dependent growth phenotypes. Unlike our published estrogen (ER) and thyroid receptor (TR) biosensors, the canonical PPARγ biosensor cells displayed pronounced growth in the absence of ligand. They were able to distinguish agonists and antagonists, however, even in the absence of agonist. To improve ligand sensitivity of this sensor, we attempted to engineer and optimize linker peptides flanking the PPARγ LBD insertion point. Truncation of the original linkers led to decreased basal growth and significantly enhanced ligand sensitivity of the PPARγ sensor, while substitution of the native linkers with optimized G(4)S (Gly-Gly-Gly-Gly-Ser) linkers further increased the sensitivity. Our studies demonstrate that the properties of linkers, especially the C-terminal linker, greatly influence the efficiency and fidelity of the allosteric signal induced by ligand binding. Our work also suggests an approach to increase allosteric behavior in this multidomain sensor protein, without modification of the functional LBD. PMID:21893405

  19. Ginsenoside Rf, a component of ginseng, regulates lipoprotein metabolism through peroxisome proliferator-activated receptor {alpha}

    SciTech Connect

    Lee, Hyunghee; Gonzalez, Frank J.; Yoon, Michung . E-mail: yoon60@mokwon.ac.kr

    2006-01-06

    We investigated whether ginseng regulates lipoprotein metabolism by altering peroxisome proliferator-activated receptor {alpha} (PPAR{alpha})-mediated pathways, using a PPAR{alpha}-null mouse model. Administration of ginseng extract, ginsenosides, and ginsenoside Rf (Rf) to wild-type mice not only significantly increased basal levels of hepatic apolipoprotein (apo) A-I and C-III mRNA compared with wild-type controls, but also substantially reversed the reductions in mRNA levels of apo A-I and C-III expected following treatment with the potent PPAR{alpha} ligand Wy14,643. In contrast, no effect was detected in the PPAR{alpha}-null mice. Testing of eight main ginsenosides on PPAR{alpha} reporter gene expression indicated that Rf was responsible for the effects of ginseng on lipoprotein metabolism. Furthermore, the inhibition of PPAR{alpha}-dependent transactivation by Rf seems to occur at the level of DNA binding. These results demonstrate that ginseng component Rf regulates apo A-I and C-III mRNA and the actions of Rf on lipoprotein metabolism are mediated via interactions with PPAR{alpha}.

  20. Activation of Peroxisome Proliferator-activated Receptor α Induces Lysosomal Biogenesis in Brain Cells

    PubMed Central

    Ghosh, Arunava; Jana, Malabendu; Modi, Khushbu; Gonzalez, Frank J.; Sims, Katherine B.; Berry-Kravis, Elizabeth; Pahan, Kalipada

    2015-01-01

    Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic interior and are central to the autophagic, endocytic, or phagocytic pathway. In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core. However, mechanisms by which TFEB is regulated are poorly understood. This study demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated receptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPARα, but not PPARβ and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB caused an increase in lysosomal protein and the lysosomal abundance in cell. Collectively, this study reinforces the link between lysosomal biogenesis and lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of therapeutic value in the treatment of lysosomal storage disorders in which autophagy-lysosome pathway plays an important role. PMID:25750174

  1. [Thiazolidinediones in type 2 diabetes. Role of peroxisome proliferator-activated receptor gamma (PPARgamma)].

    PubMed

    Dubois, M; Vantyghem, M-C; Schoonjans, K; Pattou, F

    2002-12-01

    Thiazolidinediones (TZDs) form a new class of oral antidiabetic agents. They improve insulin sensitivity and reduce glycemia, lipidemia and insulinemia in patients with type 2 diabetes. Their mechanism is original, since they activate the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARgamma), altering the expression of genes involved in glucose and lipid homeostasis. Stimulating PPARgamma improves insulin sensitivity via several mechanisms: 1) it raises the expression of GLUT4 glucose transporter; 2) it regulates release of adipocyte-derived signaling factors that affect insulin sensitivity in muscle, and 3) it contributes to a turn-over in adipose tissue, inducing the production of smaller, more insulin sensitive adipocytes. TZDs also affect free fatty acids (FFA) lipotoxicity on islets, improving pancreatic B-cell function. In addition, triglycerides and FFA levels are lowered by TZDs. Two TZDs, rosiglitazone and pioglitazone, have recently obtained the European commercial licence, but their use is restricted to the association with metformin or sulfonylureas. At the moment, they are indicated in type 2 diabetes but could be of interest in a broader array of diseases related to insulin resistance. As for side effects, rosiglitazone and pioglitazone may cause increased plasma volume, edema and dose-related weight gain. TZDs offer an attractive option in the treatment of type 2 diabetes, though it may be too soon to determine if they prevent vascular complications, as do other oral antidiabetic agents. An important issue for the future will be to assess the influence of weight gain in the long time. PMID:12527853

  2. KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.

    PubMed

    Kim, Kwang Rok; Lee, Jeong Hyung; Kim, Seung Jun; Rhee, Sang Dal; Jung, Won Hoon; Yang, Sung-Don; Kim, Sung Soo; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2006-08-14

    The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARgamma modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.

  3. Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells

    SciTech Connect

    Tsukahara, Tamotsu; Haniu, Hisao

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We examined the correlation between PPAR{gamma} expression and cell proliferation. Black-Right-Pointing-Pointer PPAR{gamma} overexpression reduces cell viability. Black-Right-Pointing-Pointer We show the synergistic effect of cell growth inhibition by a PPAR{gamma} agonist. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPAR{gamma} is expressed at considerable levels in human colon cancer cells. This suggests that PPAR{gamma} expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPAR{gamma} expression in 4 human colon cancer cell lines, HT-29, LOVO, DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPAR{gamma} mRNA and protein in these cells were in the order HT-29 > LOVO > Caco-2 > DLD-1. We also found that PPAR{gamma} overexpression promoted cell growth inhibition in PPAR{gamma} lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPAR{gamma} expression and the cells' sensitivity for proliferation.

  4. Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage.

    PubMed

    Garcia-Vallvé, Santiago; Guasch, Laura; Tomas-Hernández, Sarah; del Bas, Josep Maria; Ollendorff, Vincent; Arola, Lluís; Pujadas, Gerard; Mulero, Miquel

    2015-07-23

    Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs.

  5. Peroxisome proliferator-activated receptor agonists modulate neuropathic pain: a link to chemokines?

    PubMed Central

    Freitag, Caroline M.; Miller, Richard J.

    2014-01-01

    Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain) is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others) have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between the pain ameliorating effects of PPAR agonists and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide (PEA), shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain. PMID:25191225

  6. Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis.

    PubMed

    Lima, Emerson de Andrade; Lima, Mariana Modesto Dantas de Andrade; Marques, Cláudia Diniz Lopes; Duarte, Angela Luzia Branco Pinto; Pita, Ivan da Rocha; Pita, Maira Galdino da Rocha

    2013-01-01

    Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis.

  7. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    PubMed Central

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-01-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40%) when compared to docking with a single structure model (less than 20%). Prediction was also improved when specific protein-ligand interactions between the docked ligands and structure models were given greater weight than the calculated free energy of binding. A large-scale screen of compounds using a marketed drug database verified the predictive ability of the selected structure models. This study highlights the steps necessary to improve screening for PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development. PMID:25616366

  8. Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding.

    PubMed

    Schwarz, Rico; Tänzler, Dirk; Ihling, Christian H; Sinz, Andrea

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been intensively studied as drug targets to treat type 2 diabetes, lipid disorders, and metabolic syndrome. This study is part of our ongoing efforts to map conformational changes in PPARs in solution by a combination of chemical cross-linking and mass spectrometry (MS). To our best knowledge, we performed the first studies addressing solution structures of full-length PPAR-β/δ. We monitored the conformations of the ligand-binding domain (LBD) as well as full-length PPAR-β/δ upon binding of two agonists. (Photo-) cross-linking relied on (i) a variety of externally introduced amine- and carboxyl-reactive linkers and (ii) the incorporation of the photo-reactive amino acid p-benzoylphenylalanine (Bpa) into PPAR-β/δ by genetic engineering. The distances derived from cross-linking experiments allowed us to monitor conformational changes in PPAR-β/δ upon ligand binding. The cross-linking/MS approach proved highly advantageous to study nuclear receptors, such as PPARs, and revealed the interplay between DBD (DNA-binding domain) and LDB in PPAR-β/δ. Our results indicate the stabilization of a specific conformation through ligand binding in PPAR-β/δ LBD as well as full-length PPAR-β/δ. Moreover, our results suggest a close distance between the N- and C-terminal regions of full-length PPAR-β/δ in the presence of GW1516. Chemical cross-linking/MS allowed us gaining detailed insights into conformational changes that are induced in PPARs when activating ligands are present. Thus, cross-linking/MS should be added to the arsenal of structural methods available for studying nuclear receptors.

  9. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics

    PubMed Central

    Oh, Sun-Hee; Park, Se-Min; Park, Jong-Sook; Jang, An-Soo; Lee, Yong-Mok; Uh, Soo-Taek; Kim, Young Hoon; Choi, In-Seon; Kim, Mi-Kyeong; Park, Byeong Lae

    2009-01-01

    Purpose Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA. Methods Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His). Results Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04). Conclusions The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma. PMID:20224667

  10. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    SciTech Connect

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao; Han, Xiang Hua; Lee, Dong-Ho; Lee, Hak-Ju; Hwang, Bang Yeon; Lee, Sung-Joon

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  11. Effects of Peroxisome Proliferator-Activated Receptor-δ Agonist on Cardiac Healing after Myocardial Infarction.

    PubMed

    Park, Jeong Rang; Ahn, Jong Hwa; Jung, Myeong Hee; Koh, Jin-Sin; Park, Yongwhi; Hwang, Seok-Jae; Jeong, Young-Hoon; Kwak, Choong Hwan; Lee, Young Soo; Seo, Han Geuk; Kim, Jin Hyun; Hwang, Jin-Yong

    2016-01-01

    Peroxisome proliferator-activated receptor-delta (PPAR-δ)-dependent signaling is associated with rapid wound healing in the skin. Here, we investigated the therapeutic effects of PPAR-δ-agonist treatment on cardiac healing in post-myocardial infarction (MI) rats. Animals were assigned to the following groups: sham-operated control group, left anterior descending coronary artery ligation (MI) group, or MI with administration of the PPAR-δ agonist GW610742 group. GW610742 (1 mg/kg) was administrated intraperitoneally after the operation and repeated every 3 days. Echocardiographic data showed no differences between the two groups in terms of cardiac function and remodeling until 4 weeks. However, the degrees of angiogenesis and fibrosis after MI were significantly higher in the GW610742-treated rats than in the untreated MI rats at 1 week following MI, which changes were not different at 2 weeks after MI. Naturally, PPAR-δ expression in infarcted myocardium was highest increased in 3 day after MI and then disappeared in 14 day after MI. GW610742 increased myofibroblast differentiation and transforming growth factor-beta 2 expression in the infarct zone at 7 days after MI. GW610742 also increased bone marrow-derived mesenchymal stem cell (MSC) recruitment in whole myocardium, and increased serum platelet-derived growth factor B, stromal-derived factor-1 alpha, and matrix metallopeptidase 9 levels at day 3 after MI. PPAR-δ agonists treatment have the temporal effect on early fibrosis of infarcted myocardium, which might not sustain the functional and structural beneficial effect. PMID:26862756

  12. Peroxisome proliferator-activated receptor β/δ induces myogenesis by modulating myostatin activity.

    PubMed

    Bonala, Sabeera; Lokireddy, Sudarsanareddy; Arigela, Harikumar; Teng, Serena; Wahli, Walter; Sharma, Mridula; McFarlane, Craig; Kambadur, Ravi

    2012-04-13

    Classically, peroxisome proliferator-activated receptor β/δ (PPARβ/δ) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPARβ/δ during skeletal muscle growth and regeneration. Although PPARβ/δ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPARβ/δ in regulating postnatal myogenesis. Here we report for the first time, using a PPARβ/δ-specific ligand (L165041) and the PPARβ/δ-null mouse model, that PPARβ/δ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPARβ/δ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPARβ/δ-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPARβ/δ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPARβ/δ. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPARβ/δ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPARβ/δ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1. PMID:22362769

  13. Suppression of Rat Oral Carcinogenesis by Agonists of Peroxisome Proliferator Activated Receptor γ

    PubMed Central

    McCormick, David L.; Horn, Thomas L.; Johnson, William D.; Peng, Xinjian; Lubet, Ronald A.; Steele, Vernon E.

    2015-01-01

    Peroxisome-proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that regulates cell proliferation, differentiation, and apoptosis. In vivo studies were performed to evaluate the activities of two thiazolidinedione PPARγ agonists, rosiglitazone and pioglitazone, as inhibitors of oral carcinogenesis in rats. Oral squamous cell carcinomas (OSCC) were induced in male F344 rats by 4-nitroquinoline-1-oxide (NQO; 20 ppm in the drinking water for 10 weeks). In each study, groups of 30 NQO-treated rats were exposed to a PPARγ agonist beginning at week 10 (one day after completion of NQO administration) or at week 17 (7 weeks post-NQO); chemopreventive agent exposure was continued until study termination at week 22 (rosiglitazone study) or week 24 (pioglitazone study). Administration of rosiglitazone (800 mg/kg diet) beginning at week 10 increased survival, reduced oral cancer incidence, and reduced oral cancer invasion score in comparison to dietary controls; however, chemopreventive activity was largely lost when rosiglitazone administration was delayed until week 17. Administration of pioglitazone (500 mg/kg diet beginning at week 10 or 1000 mg/kg diet beginning at week 17) induced significant reductions in oral cancer incidence without significant effects on OSCC invasion scores. Transcript levels of PPARγ and its three transcriptional variants (PPARγv1, PPARγv2, and PPARγv3) were not significantly different in OSCC versus age- and site-matched phenotypically normal oral tissues from rats treated with NQO. These data suggest that PPARγ provides a useful molecular target for oral cancer chemoprevention, and that overexpression of PPARγ at the transcriptional level in neoplastic lesions is not essential for chemopreventive efficacy. PMID:26516762

  14. Lung injury after hemorrhage is age-dependent: role of peroxisome proliferator activated receptor γ

    PubMed Central

    Zingarelli, Basilia; Hake, Paul W.; O’Connor, Michael; Burroughs, Timothy J.; Wong, Hector R.; Solomkin, Joseph S.; Lentsch, Alex B.

    2009-01-01

    Objective The incidence of multiple organ failure in pediatric trauma victims is lower than in the adult population. However, the molecular mechanisms are not yet defined. We investigated whether the pathophysiologic characteristics of hemorrhage-induced lung injury may be age-dependent and may be regulated by the peroxisome proliferator activator receptor γ (PPARγ). Design Prospective, laboratory investigation that used an established rodent model of hemorrhagic shock. Setting University hospital laboratory. Subjects Young (n=67; 3–5 months old) and mature (n=66; 11–13 months old) male rats. Interventions Hemorrhagic shock was induced in young and mature rats by withdrawing blood to a mean arterial blood pressure of 50 mmHg. After 3 hrs, rats were rapidly resuscitated by infusing the shed blood and sacrificed 3 hrs thereafter. Measurements and Main Results In young rats, lung injury was characterized by accumulation of red cells and neutrophils at the end of the resuscitation period; at Western blot analysis, lung expression of intercellular adhesion molecule-1 (ICAM-1) was increased. In contrast, the severity of lung injury was more pronounced in mature rats. Lung myeloperoxidase activity and expression of constitutive and inducible ICAM-1 was significantly higher in mature rats when compared to young rats. Mature rats also had higher plasma levels of cytokines and chemokines when compared to young rats. This heightened inflammation was associated with higher degree of activation of nuclear factor-κB and down-regulation of PPARγ and heat shock factor-1 in the lung of mature rats when compared to young rats. Treatment with the PPARγ ligand, the cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2, ameliorated lung injury in young, but not in mature animals. Conclusions Lung injury after severe hemorrhage is age-dependent and may be secondary to a diverse regulation of PPARγ. PMID:19384226

  15. Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding.

    PubMed

    Schwarz, Rico; Tänzler, Dirk; Ihling, Christian H; Sinz, Andrea

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been intensively studied as drug targets to treat type 2 diabetes, lipid disorders, and metabolic syndrome. This study is part of our ongoing efforts to map conformational changes in PPARs in solution by a combination of chemical cross-linking and mass spectrometry (MS). To our best knowledge, we performed the first studies addressing solution structures of full-length PPAR-β/δ. We monitored the conformations of the ligand-binding domain (LBD) as well as full-length PPAR-β/δ upon binding of two agonists. (Photo-) cross-linking relied on (i) a variety of externally introduced amine- and carboxyl-reactive linkers and (ii) the incorporation of the photo-reactive amino acid p-benzoylphenylalanine (Bpa) into PPAR-β/δ by genetic engineering. The distances derived from cross-linking experiments allowed us to monitor conformational changes in PPAR-β/δ upon ligand binding. The cross-linking/MS approach proved highly advantageous to study nuclear receptors, such as PPARs, and revealed the interplay between DBD (DNA-binding domain) and LDB in PPAR-β/δ. Our results indicate the stabilization of a specific conformation through ligand binding in PPAR-β/δ LBD as well as full-length PPAR-β/δ. Moreover, our results suggest a close distance between the N- and C-terminal regions of full-length PPAR-β/δ in the presence of GW1516. Chemical cross-linking/MS allowed us gaining detailed insights into conformational changes that are induced in PPARs when activating ligands are present. Thus, cross-linking/MS should be added to the arsenal of structural methods available for studying nuclear receptors. PMID:26992147

  16. Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice

    PubMed Central

    2013-01-01

    Background Peroxisome proliferator activated receptor alpha (PPARα) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARα in ethanol induced liver fibrosis in mice. Methods C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARα agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARα induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed. Results The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARα and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury. Conclusions The present study provides evidence for the protective role of PPARα induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors. PMID:23388073

  17. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    SciTech Connect

    Mitterberger, Maria C.; Kim, Geumsoo; Rostek, Ursula; Levine, Rodney L.; Zwerschke, Werner

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.

  18. Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors.

    PubMed

    Qin, Jun; Le, Yicong; Froogh, Ghezal; Kandhi, Sharath; Jiang, Houli; Luo, Meng; Sun, Dong; Huang, An

    2016-06-01

    Epoxyeicosatrienoic acids (EETs) are cardioprotective mediators metabolized by soluble epoxide hydrolase (sEH) to form corresponding diols (DHETs). As a sex-susceptible target, sEH is involved in the sexually dimorphic regulation of cardiovascular function. Thus, we hypothesized that the female sex favors EET-mediated potentiation of cardiac function via downregulation of sEH expression, followed by upregulation of peroxisome proliferator-activated receptors (PPARs). Hearts were isolated from male (M) and female (F) wild-type (WT) and sEH-KO mice, and perfused with constant flow at different preloads. Basal coronary flow required to maintain the perfusion pressure at 100 mmHg was significantly greater in females than males, and sEH-KO than WT mice. All hearts displayed a dose-dependent decrease in coronary resistance and increase in cardiac contractility, represented as developed tension in response to increases in preload. These responses were also significantly greater in females than males, and sEH-KO than WT 14,15-EEZE abolished the sex-induced (F vs. M) and transgenic model-dependent (KO vs. WT) differences in the cardiac contractility, confirming an EET-driven response. Compared with M-WT controls, F-WT hearts expressed downregulation of sEH, associated with increased EETs and reduced DHETs, a pattern comparable to that observed in sEH-KO hearts. Coincidentally, F-WT and sEH-KO hearts exhibited increased PPARα expression, but comparable expression of eNOS, PPARβ, and EET synthases. In conclusion, female-specific downregulation of sEH initiates an EET-dependent adaptation of cardiac function, characterized by increased coronary flow via reduction in vascular resistance, and promotion of cardiac contractility, a response that could be further intensified by PPARα.

  19. Interaction between peroxisome proliferator-activated receptor gamma and smoking on cardiovascular disease.

    PubMed

    Ding, Xiang; Wang, Rong; Liu, Li; Yu, Qiushi; Wang, Zhiquan; Ma, Zhiqiang; Zhu, Qiming

    2016-01-01

    The aim of this study was to investigate the association between peroxisome proliferator-activator receptor-γ (PPAR-γ) genotype and additional gene-smoking interaction on cardiovascular disease (CVD) based on a Chinese population. A total of 1248 subjects (613 men, 635 women), with a mean age of 55.5±11.8 years old, were selected, including 620 CVD patients and 628 normal controls. Logistic regression was performed to investigate association between single nucleotide polymorphism (SNP) and CVD. Generalized MDR (GMDR) was used to analysis the gene-environment interaction, cross-validation consistency, the testing balanced accuracy, and the sign test, to assess each selected interaction were calculated. The carriers of homozygous mutant of two SNP revealed increased CVD risk than those with wild-type homozygotes, OR (95% CI) were 1.31 (1.16-1.95) and 1.68 (1.29-2.06), respectively. GMDR analysis for one- to three-locus models indicated that there was a significant two-locus model (p=0.0107) involving rs1805192 and smoking, indicating a potential gene-gene interaction between rs1805192 and smoking. Overall, the two- locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 62.17%. We found that smokers with Pro/Ala or Ala/Ala genotype have highest CVD risk, compared to non-smokers with Pro/Pro genotype, OR (95% CI) was 3.46 (1.31-3.42), after covariates adjustment. We found a significant association between genotypes of variants in rs10865710 and rs1805192 with increased CVD risk and a potential gene-gene interaction between rs1805192 and smoking.

  20. Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding

    PubMed Central

    Schwarz, Rico; Tänzler, Dirk; Ihling, Christian H.; Sinz, Andrea

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been intensively studied as drug targets to treat type 2 diabetes, lipid disorders, and metabolic syndrome. This study is part of our ongoing efforts to map conformational changes in PPARs in solution by a combination of chemical cross-linking and mass spectrometry (MS). To our best knowledge, we performed the first studies addressing solution structures of full-length PPAR-β/δ. We monitored the conformations of the ligand-binding domain (LBD) as well as full-length PPAR-β/δ upon binding of two agonists. (Photo-) cross-linking relied on (i) a variety of externally introduced amine- and carboxyl-reactive linkers and (ii) the incorporation of the photo-reactive amino acid p-benzoylphenylalanine (Bpa) into PPAR-β/δ by genetic engineering. The distances derived from cross-linking experiments allowed us to monitor conformational changes in PPAR-β/δ upon ligand binding. The cross-linking/MS approach proved highly advantageous to study nuclear receptors, such as PPARs, and revealed the interplay between DBD (DNA-binding domain) and LDB in PPAR-β/δ. Our results indicate the stabilization of a specific conformation through ligand binding in PPAR-β/δ LBD as well as full-length PPAR-β/δ. Moreover, our results suggest a close distance between the N- and C-terminal regions of full-length PPAR-β/δ in the presence of GW1516. Chemical cross-linking/MS allowed us gaining detailed insights into conformational changes that are induced in PPARs when activating ligands are present. Thus, cross-linking/MS should be added to the arsenal of structural methods available for studying nuclear receptors. PMID:26992147

  1. Role of peroxisome proliferator-activated receptor-α in acute pancreatitis induced by cerulein

    PubMed Central

    Genovese, Tiziana; Mazzon, Emanuela; Di Paola, Rosanna; Muià, Carmelo; Crisafulli, Concetta; Malleo, Giuseppe; Esposito, Emanuela; Cuzzocrea, Salvatore

    2006-01-01

    The peroxisome proliferator-activated receptor-α (PPAR-α) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid and thyroid hormone receptors. The aim of the present study was to examine the effects of endogenous PPAR-α ligand on the development of acute pancreatitis caused by cerulein in mice. Intraperitoneal injection of cerulein into PPAR-α wild-type (WT) mice resulted in severe, acute pancreatitis characterized by oedema, neutrophil infiltration and necrosis and by elevated serum levels of amylase and lipase. Infiltration of pancreatic and lung tissue with neutrophils (measured as an increase in myeloperoxidase activity) was associated with enhanced expression of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and P-selectin. Immunohistochemical examination demonstrated a marked increase in the staining (immunoreactivity) for transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) in the pancreas of cerulein-treated PPAR-α wild-type (WT) mice in comparison to sham-treated mice. Acute pancreatitis in PPAR-αWT mice was also associated with a significant mortality (20% survival at 5 days after cerulein administration). In contrast, the degree of pancreatic inflammation and tissue injury (histological score), up-regulation/formation of ICAM-1 and P-selectin, infiltration of neutrophils, and the expression of TGF-β and VEGF was markedly enhanced in pancreatic tissue obtained from cerulein-treated PPAR-α knockout (KO) mice. Thus, endogenous PPAR-α ligands reduce the degree of pancreas injury caused by acute pancreatitis induced by cerulein administration. PMID:16764691

  2. Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity.

    PubMed

    Shin, Hyoung Doo; Park, Byung Lae; Kim, Lyoung Hyo; Jung, Hye Seung; Cho, Young Min; Moon, Min Kyong; Park, Young Joo; Lee, Hong Kyu; Park, Kyong Soo

    2004-03-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases. PMID:14988273

  3. A widely used retinoic acid receptor antagonist induces peroxisome proliferator-activated receptor-gamma activity.

    PubMed

    Schupp, Michael; Curtin, Joshua C; Kim, Roy J; Billin, Andrew N; Lazar, Mitchell A

    2007-05-01

    Nuclear receptors (NRs) are transcription factors whose activity is regulated by the binding of small lipophilic ligands, including hormones, vitamins, and metabolites. Pharmacological NR ligands serve as important therapeutic agents; for example, all-trans retinoic acid, an activating ligand for retinoic acid receptor alpha (RARalpha), is used to treat leukemia. Another RARalpha ligand, (E)-S,S-dioxide-4-(2-(7-(heptyloxy)-3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-6-yl)-1-propenyl)-benzoic acid (Ro 41-5253), is a potent antagonist that has been a useful and purportedly specific probe of RARalpha function. Here, we report that Ro 41-5253 also activates the peroxisome proliferator-activated receptor gamma (PPARgamma), a master regulator of adipocyte differentiation and target of widely prescribed antidiabetic thiazolidinediones (TZDs). Ro 41-5253 enhanced differentiation of mouse and human preadipocytes and activated PPARgamma target genes in mature adipocytes. Like the TZDs, Ro 41-5253 also down-regulated PPARgamma protein expression in adipocytes. In addition, Ro 41-5253 activated the PPARgamma-ligand binding domain in transiently transfected HEK293T cells. These effects were not prevented by a potent RARalpha agonist or by depleting cells of RARalpha, indicating that PPARgamma activation was not related to RARalpha antagonism. Indeed, Ro 41-5253 was able to compete with TZD ligands for binding to PPARgamma, suggesting that Ro 41-5253 directly affects PPAR activity. These results vividly demonstrate that pharmacological NR ligands may have "off-target" effects on other NRs. Ro 41-5253 is a PPARgamma agonist as well as an RARalpha antagonist whose pleiotropic effects on NRs may signify a unique spectrum of biological responses.

  4. Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium

    EPA Science Inventory

    The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents inc...

  5. Peroxisome proliferator-activated receptor alpha (PPARalpha) agonists down-regulate alpha2-macroglobulin expression by a PPARalpha-dependent mechanism.

    EPA Science Inventory

    Peroxisome proliferator-activated receptor alpha (PPARα) regulates transcription of genes involved both in lipid and glucose metabolism as well as inflammation. Fibrates are PPARα ligands used to normalize lipid and glucose parameters and exert anti-inflammatory effects. Fibrates...

  6. PEROXISOME-PROLIFERATOR ACTIVATED RECEPTORS AS A MACROMOLECULAR TARGET FOR CHEMICAL TOXICITY: MODELS OF THE INTERACTIONS OF PPARS WITH PERFLUORINATED ORGANIC COMPOUNDS.

    EPA Science Inventory

    The Peroxisome Proliferator Activated Receptors (PPARs), a class of nuclear receptors that modulate both transcription and metabolic processes, are implicated in a variety of metabolic disorders linked to lipidogenesis, adipose tissue accumulation, fatty-acid oxidation pathways, ...

  7. ACTIVATION OF MOUSE AND HUMAN PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPAR ALPHA, GAMMA, BETA DELTA) BY PERFLUOROOCTANOIC ACID (PFOA) AND PERFLUOROOCTANE SULFONATE (PFOS)

    EPA Science Inventory

    This study evaluates the potential for perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) to activate peroxisome proliferator-activated receptors (PPARs), using a transient transfection cell assay. Cos-1 cells were cultured in DMEM with fetal bovine serum (FBS) in ...

  8. Review of the expression of Peroxisome Proliferator Activated Receptors alpha (PPARα), beta (PPAR β), and gamma (PPAR() in rodent and human development.

    EPA Science Inventory

    The peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily and there are three primary isotypes, PPARα, β, and (. These receptors regulate important physiological processes that impact lipid homeostasis, inflammation, adipogenesis, r...

  9. Analysis of the Heat Shock Response in Mouse Liver Reveals Transcriptional Dependence on the Nuclear Receptor Peroxisome Proliferator-Activated Receptor alpha (PPARα)

    EPA Science Inventory

    BACKGROUND: The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by h...

  10. Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

    SciTech Connect

    Zhang, Lianying; Ren, Xiao-Min; Wan, Bin; Guo, Liang-Hong

    2014-09-15

    Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.

  11. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production

    PubMed Central

    Colin, Sophie; Briand, Olivier; Touche, Véronique; Wouters, Kristiaan; Baron, Morgane; Pattou, François; Hanf, Rémy; Tailleux, Anne; Chinetti, Giulia; Staels, Bart; Lestavel, Sophie

    2013-01-01

    Aims Peroxisome Proliferator-Activated Receptor (PPAR) α is a transcription factor controlling lipid metabolism in liver, heart, muscle and macrophages. PPARα-activation increases plasma HDL-cholesterol and exerts hypotriglyceridemic actions via the liver. However, the intestine expresses PPARα, produces HDL and chylomicrons and is exposed to diet-derived PPARα ligands. Therefore, we examined the effects of PPARα-activation on intestinal lipid and lipoprotein metabolism. Methods and Results The impact of PPARα-activation was evaluated in term of HDL-related gene expression in mice, ex-vivo in human jejunal biopsies and in Caco-2/TC7 cells. ApoAI/HDL secretion, cholesterol esterification and trafficking were also studied in-vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty-acid-oxidation genes, treatment with the dual PPARα/δ-ligand GFT505 resulted in a more pronounced increase of plasma HDL compared to fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL-production genes such as apolipoprotein-AI and ATP-Binding-Cassette-A1 transporter in murine intestines. A similar increase was observed upon PPARα-activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPARα-activation decreased the cholesterol-esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking and reduced apolipoprotein-B secretion. Conclusions PPARα-activation reduces cholesterol esterification, suppresses chylomicron- and increases HDL-secretion by enterocytes. These results identify the intestine as a target organ of PPARα-ligands with entero-hepatic tropism to reduce atherogenic dyslipidemia. PMID:22843443

  12. Peroxisome proliferator-activated receptor gamma (PPARG) polymorphisms and breast cancer susceptibility: a meta-analysis

    PubMed Central

    Tang, Weifeng; Chen, Yuanmei; Wang, Yafeng; Gu, Haiyong; Chen, Shuchen; Kang, Mingqiang

    2015-01-01

    Background: Peroxisome proliferator-activated receptor gamma (PPARG), a nuclear hormone receptor, plays a critical role in the lipid and glucose homeostasis, adipocyte differentiation, as well as intracellular insulin-signaling events. Several studies have been conducted to explore the associations of PPARG polymorphisms with breast cancer (BC), yet the findings are inconsistent. Methods: Databases of Pubmed and Embase were searched until October 5, 2014. The association between PPARG polymorphisms and BC risk was determined by crude odds ratios (ORs) with their 95% confidence intervals (CIs). Results: Finally, there are nine publications involving 3,931 BC cases and 5,382 controls included in this meta-analysis. No significant association was observed between PPARG rs1801282 C>G variants and overall BC risk in all genetic comparison models. However, in a subgroup analysis by ethnicity, significant association was observed between PPARG rs1801282 C>G variants and decreased BC risk in three genetic models: GG+CG vs. CC (OR, 0.83; 95% CI, 0.71-0.96; P = 0.011), CG vs. CC (OR, 0.82; 95% CI, 0.71-0.96; P = 0.011) and G vs. C (OR, 0.85; 95% CI, 0.75-0.97; P = 0.016) in Caucasians and in a subgroup analysis by menopausal status, significantly decreased BC risk was also found in two genetic models: GG+CG vs. CC (OR, 0.79; 95% CI, 0.67-0.95; P = 0.011) and CG vs. CC (OR, 0.77; 95% CI, 0.64-0.92; P = 0.005) in post-menopause subgroup. For PPARG rs3856806 C>T, we found no significant association between PPARG rs3856806 C>T polymorphism and breast cancer. Conclusions: In summary, despite some limitations, the results suggest that PPARG rs1801282 C>G polymorphism may be a protective factor for BC in Caucasians and in post-menopause women. PMID:26550133

  13. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    SciTech Connect

    Hasegawa-Moriyama, Maiko; Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  14. Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

    SciTech Connect

    Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki; Kawada, Teruo

    2011-04-22

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected

  15. Molecular Recognition of Agonist and Antagonist for Peroxisome Proliferator-Activated Receptor-α Studied by Molecular Dynamics Simulations

    PubMed Central

    Liu, Mengyuan; Wang, Lushan; Zhao, Xian; Sun, Xun

    2014-01-01

    Peroxisome proliferator activated receptor-α (PPAR-α) is a ligand-activated transcription factor which plays important roles in lipid and glucose metabolism. The aim of this work is to find residues which selectively recognize PPAR-α agonists and antagonists. To achieve this aim, PPAR-α/13M and PPAR-α/471 complexes were subjected to perform molecular dynamics simulations. This research suggests that several key residues only participate in agonist recognition, while some other key residues only contribute to antagonist recognition. It is hoped that such work is useful for medicinal chemists to design novel PPAR-α agonists and antagonists. PMID:24837836

  16. Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy

    PubMed Central

    Wagner, Kay-Dietrich; Vukolic, Ana; Baudouy, Delphine; Michiels, Jean-François

    2016-01-01

    Peroxisome proliferator-activated receptors are nuclear receptors which function as ligand-activated transcription factors. Among them, peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in the heart and thought to have cardioprotective functions due to its beneficial effects in metabolic syndrome. As we already showed that PPARβ/δ activation resulted in an enhanced cardiac angiogenesis and growth without impairment of heart function, we were interested to determine the effects of a specific activation of PPARβ/δ in the vasculature on cardiac performance under normal and in chronic ischemic heart disease conditions. We analyzed the effects of a specific PPARβ/δ overexpression in endothelial cells on the heart using an inducible conditional vascular-specific mouse model. We demonstrate that vessel-specific overexpression of PPARβ/δ induces rapid cardiac angiogenesis and growth with an increase in cardiomyocyte size. Upon myocardial infarction, vascular overexpression of PPARβ/δ, despite the enhanced cardiac vessel formation, does not protect against chronic ischemic injury. Our results suggest that the proper balance of PPARβ/δ activation in the different cardiac cell types is required to obtain beneficial effects on the outcome in chronic ischemic heart disease. PMID:27057154

  17. MECHANISMS INVOLVED IN THE ENHANCED SUSCEPTIBILITY OF SENESCENT RATS TO THE HEPATOCARCINOGENIC EFFECT OF PEROXISOME PROLIFERATORS: ROLE OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA (PPARA), CELL PROLIFERATION AND OXIDATIVE STRESS

    EPA Science Inventory

    Mechanisms involved in the ENHANCED SUSCEPTIBILITY of SENESCENT Rats TO THE HEPATOCARCINOGENIC EFFECT OF PEROXISOME PROLIFERATORS: Role of peroxisome proliferator-activated receptor alpha (PPARa), cell proliferation and oxidative stress

    Jihan A. Youssef1, Pierre Ammann2, B...

  18. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    SciTech Connect

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu; Yoo, Kyeong-Won; Song, Seung Ryel; Park, Do-Sim; So, Hong-Seob; Park, Raekil

    2013-12-06

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

  19. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo

    PubMed Central

    Mazidi, Mohsen; Karimi, Ehsan; Meydani, Mohsen; Ghayour-Mobarhan, Majid; Ferns, Gordon A

    2016-01-01

    Natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported (using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ. PMID:27019802

  20. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo.

    PubMed

    Mazidi, Mohsen; Karimi, Ehsan; Meydani, Mohsen; Ghayour-Mobarhan, Majid; Ferns, Gordon A

    2016-03-26

    Natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported (using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ. PMID:27019802

  1. Peroxisome Proliferator-Activated Receptor (PPAR) in Regenerative Medicine: Molecular Mechanism for PPAR in Stem Cells' Adipocyte Differentiation.

    PubMed

    Xie, Qiang; Tian, Taoran; Chen, Zhaozhao; Deng, Shuwen; Sun, Ke; Xie, Jing; Cai, Xiaoxiao

    2016-01-01

    Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.

  2. Pioglitazone Suppresses CXCR7 Expression To Inhibit Human Macrophage Chemotaxis through Peroxisome Proliferator-Activated Receptor γ.

    PubMed

    Zhao, Duo; Zhu, Zhicheng; Li, Dan; Xu, Rihao; Wang, Tiance; Liu, Kexiang

    2015-11-17

    Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Pioglitazone, the widely used thiazolidinedione, is shown to be efficient in the prevention of cardiovascular complications of T2DM. In this study, we report that pioglitazone inhibits CXCR7 expression and thus blocks chemotaxis in differentiated macrophage without perturbing cell viability or macrophage differentiation. In addition, pioglitazone-mediated CXCR7 suppression and chemotaxis inhibition occur via activating peroxisome proliferator-activated receptor γ (PPARγ) but not PPARα in differentiated macrophage. More importantly, pioglitazone therapy-induced PPARγ activation suppresses CXCR7 expression in human carotid atherosclerotic lesions. Collectively, our data demonstrate that pioglitazone suppresses CXCR7 expression to inhibit human macrophage chemotaxis through PPARγ.

  3. Letter: Iatrogenic lipomatosis: a rare manifestation of treatment with a peroxisome proliferator-activated receptor gamma agonist.

    PubMed

    Femia, Alisa; Klein, Peter A

    2010-04-15

    Lipomas are common benign neoplasms of adipose tissue. Lipomatosis, the progressive appearance of multiple lipomas, is most often associated with specific congenital, familial, or idiopathic syndromes. In one reported case, the development of multiple lipomas occurred as a result of treatment with rosiglitazone, a peroxisome proliferator-activated receptor (PPAR) gamma agonist. We report a second case of lipomatosis occurring as a result of treatment with a PPAR gamma agonist. This case occurred in a 77-year-old woman who developed multiple lipomas two years after beginning treatment with pioglitazone, a PPAR gamma agonist. Histopathologic examination confirmed these lesions to be lipomas. Within four weeks of discontinuation of pioglitazone, regression of the lipomas began. We describe a case of PPAR agonist-induced lipoma formation, review relevant literature, and provide a molecular mechanism for this side effect.

  4. Sleep and neurochemical modulation by the nuclear peroxisome proliferator-activated receptor α (PPAR-α) in rat.

    PubMed

    Mijangos-Moreno, Stephanie; Poot-Aké, Alwin; Guzmán, Khalil; Arankowsky-Sandoval, Gloria; Arias-Carrión, Oscar; Zaldívar-Rae, Jaime; Sarro-Ramírez, Andrea; Murillo-Rodríguez, Eric

    2016-04-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear protein that plays an essential role in diverse neurobiological processes. However, the role of PPARα on the sleep modulation is unknown. Here, rats treated with an intrahypothalamic injection of Wy14643 (10μg/1μL; PPARα agonist) enhanced wakefulness and decreased slow wave sleep and rapid eye movement sleep whereas MK-886 (10μg/1μL; PPARα antagonist) promoted opposite effects. Moreover, Wy14643 increased dopamine, norepinephrine, serotonin, and adenosine contents collected from nucleus accumbens. The levels of these neurochemicals were diminished after MK-886 treatment. The current findings suggest that PPARα may participate in the sleep and neurochemical modulation. PMID:26450400

  5. Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

    PubMed

    Ammazzalorso, Alessandra; Carrieri, Antonio; Verginelli, Fabio; Bruno, Isabella; Carbonara, Giuseppe; D'Angelo, Alessandra; De Filippis, Barbara; Fantacuzzi, Marialuigia; Florio, Rosalba; Fracchiolla, Giuseppe; Giampietro, Letizia; Giancristofaro, Antonella; Maccallini, Cristina; Cama, Alessandro; Amoroso, Rosa

    2016-05-23

    Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism. PMID:26974385

  6. Expression regulation and targeting of the peroxisome proliferator-activated receptor γ following electrically-induced status epilepticus.

    PubMed

    Boes, Katharina; Russmann, Vera; Ongerth, Tanja; Licko, Thomas; Salvamoser, Josephine D; Siegl, Claudia; Potschka, Heidrun

    2015-09-14

    The neuroprotective and anti-inflammatory effects of the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone are of particular interest for disease-modifying and antiepileptogenic approaches. We studied the expression of PPARγ and the impact of rosiglitazone on the consequences of status epilepticus (SE) in a rat post-SE model. Immunohistochemical analysis revealed a selective overexpression of PPARγ in the piriform cortex of rats with spontaneous seizures. Rosiglitazone administration initiated following SE failed to exert relevant effects on the development of spontaneous seizures and neuronal cell loss. Whereas spatial learning in the Morris water maze was delayed in SE animals with vehicle administration, the learning curve of rosiglitazone-treated SE rats showed no significant difference to that of controls. The study provides first evidence arguing against a robust antiepileptogenic effect. However, the findings in the spatial learning paradigm indicate disease-modifying effects. PMID:26259695

  7. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates promyogenic signaling pathways, thereby promoting myoblast differentiation.

    PubMed

    Lee, Sang-Jin; Go, Ga-Yeon; Yoo, Miran; Kim, Yong Kee; Seo, Dong-Wan; Kang, Jong-Sun; Bae, Gyu-Un

    2016-01-29

    Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) regulates postnatal myogenesis by alleviating myostatin activity, but the molecular mechanisms by which it regulates myogenesis are not fully understood. In this study, we investigate molecular mechanisms of PPARβ/δ in myoblast differentiation. C2C12 myoblasts treated with a PPARβ/δ agonist, GW0742 exhibit enhanced myotube formation and muscle-specific gene expression. GW0742 treatment dramatically activates promyogenic kinases, p38MAPK and Akt, in a dose-dependent manner. GW0742-stimulated myoblast differentiation is mediated by p38MAPK and Akt, since it failed to restore myoblast differentiation repressed by inhibition of p38MAPK and Akt. In addition, GW0742 treatment enhances MyoD-reporter activities. Consistently, overexpression of PPARβ/δ enhances myoblast differentiation accompanied by elevated activation of p38MAPK and Akt. Collectively, these results suggest that PPARβ/δ enhances myoblast differentiation through activation of promyogenic signaling pathways.

  8. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo.

    PubMed

    Mazidi, Mohsen; Karimi, Ehsan; Meydani, Mohsen; Ghayour-Mobarhan, Majid; Ferns, Gordon A

    2016-03-26

    Natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported (using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ.

  9. Sphingosine 1-phosphate is a ligand for peroxisome proliferator-activated receptor-γ that regulates neoangiogenesis.

    PubMed

    Parham, Kate A; Zebol, Julia R; Tooley, Katie L; Sun, Wai Y; Moldenhauer, Lachlan M; Cockshell, Michaelia P; Gliddon, Briony L; Moretti, Paul A; Tigyi, Gabor; Pitson, Stuart M; Bonder, Claudine S

    2015-09-01

    Sphingosine 1-phosphate (S1P) is a bioactive lipid that can function both extracellularly and intracellularly to mediate a variety of cellular processes. Using lipid affinity matrices and a radiolabeled lipid binding assay, we reveal that S1P directly interacts with the transcription factor peroxisome proliferator-activated receptor (PPAR)γ. Herein, we show that S1P treatment of human endothelial cells (ECs) activated a luciferase-tagged PPARγ-specific gene reporter by ∼12-fold, independent of the S1P receptors. More specifically, in silico docking, gene reporter, and binding assays revealed that His323 of the PPARγ ligand binding domain is important for binding to S1P. PPARγ functions when associated with coregulatory proteins, and herein we identify that peroxisome proliferator-activated receptor-γ coactivator 1 (PGC1)β binds to PPARγ in ECs and their progenitors (nonadherent endothelial forming cells) and that the formation of this PPARγ:PGC1β complex is increased in response to S1P. ECs treated with S1P selectively regulated known PPARγ target genes with PGC1β and plasminogen-activated inhibitor-1 being increased, no change to adipocyte fatty acid binding protein 2 and suppression of CD36. S1P-induced in vitro tube formation was significantly attenuated in the presence of the PPARγ antagonist GW9662, and in vivo application of GW9662 also reduced vascular development in Matrigel plugs. Interestingly, activation of PPARγ by the synthetic ligand troglitazone also reduced tube formation in vitro and in vivo. To support this, Sphk1(-/-)Sphk2(+/-) mice, with low circulating S1P levels, demonstrated a similar reduction in vascular development. Taken together, our data reveal that the transcription factor, PPARγ, is a bona fide intracellular target for S1P and thus suggest that the S1P:PPARγ:PGC1β complex may be a useful target to manipulate neovascularization.

  10. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences.

    PubMed

    Saha, Lekha

    2015-11-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy

  11. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences

    PubMed Central

    Saha, Lekha

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identified so far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs (e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system (e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Ligand-dependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy

  12. Effects of the interaction of diabetes and iron supplementation on hepatic and pancreatic tissues, oxidative stress markers, and liver peroxisome proliferator-activated receptor-α expression

    PubMed Central

    Silva, Maísa; Bonomo, Larissa de Freitas; Oliveira, Riva de Paula; Geraldo de Lima, Wanderson; Silva, Marcelo Eustáquio; Pedrosa, Maria Lucia

    2011-01-01

    This study evaluated the effects of the interaction of diabetes and a carbonyl iron supplemented on hepatic and pancreatic tissues, oxidative stress markers and liver peroxisome proliferator-activated receptor-α expressions. Hamsters were divided: Control which received a standard AIN 93 diet; Control Iron, composed of control animals that received a diet with 0.83% carbonyl iron; Diabetic, composed of animals that received a injection of streptozotocin (50 mg/kg, intraperitoneal) on day 35; and Diabetic Iron composed of streptozotocin treated animals that received a diet supplemented with carbonyl iron. Diabetes increased the glucose level and reduced triglycerides. Diabetic Iron group showed higher levels of glucose and serum triglycerides as compared to the Diabetic group. Diabetes decreased mRNA levels of peroxisome proliferator-activated receptor-α. Iron attenuated the diabetes induced down regulation of peroxisome proliferator-activated receptor-α mRNA. Moreover, diabetes increased carbonyl protein and decreased glutathione levels and catalase activity, while iron attenuated the increase in levels of carbonyl protein and attenuated the decrease in those of glutathione level and catalase activity. Histological analysis shows that supplementation iron caused an increase in the size of the islets in Control Iron. The results show that iron does not aggravated liver oxidant/antioxidant status and peroxisome proliferator-activated receptor-α expression in diabetic hamsters. PMID:21980225

  13. EFFECTS OF CHRONIC ACTIVATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA OR HIGH-FAT FEEDING IN A RAT INFARCT MODEL OF HEART FAILURE

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Intracardiac accumulation of lipid and related intermediates (e.g., ceramide) is associated with cardiac dysfunction and may contribute to the progression of heart failure (HF). Overexpression of nuclear receptor peroxisome proliferator-activated receptor-alpha (PPAR-alpha) increases intramyocellula...

  14. Peroxisome Proliferator-Activated Receptor γ Is a Target for Halogenated Analogs of Bisphenol A

    PubMed Central

    Riu, Anne; Grimaldi, Marina; le Maire, Albane; Bey, Gilbert; Phillips, Kevin; Boulahtouf, Abdelhay; Perdu, Elisabeth; Zalko, Daniel; Bourguet, William

    2011-01-01

    Background: The occurrence of halogenated analogs of the xenoestrogen bisphenol A (BPA) has been recently demonstrated both in environmental and human samples. These analogs include brominated [e.g., tetrabromobisphenol A (TBBPA)] and chlorinated [e.g., tetrachlorobisphenol A (TCBPA)] bisphenols, which are both flame retardants. Because of their structural homology with BPA, such chemicals are candidate endocrine disruptors. However, their possible target(s) within the nuclear hormone receptor superfamily has remained unknown. Objectives: We investigated whether BPA and its halogenated analogs could be ligands of estrogen receptors (ERs) and peroxisome proliferator–activated receptors (PPARs) and act as endocrine-disrupting chemicals. Methods: We studied the activity of compounds using reporter cell lines expressing ERs and PPARs. We measured the binding affinities to PPARγ by competitive binding assays with [3H]-rosiglitazone and investigated the impact of TBBPA and TCBPA on adipocyte differentiation using NIH3T3-L1 cells. Finally, we determined the binding mode of halogenated BPAs to PPARγ by X-ray crystallography. Results: We observed that TBBPA and TCBPA are human, zebrafish, and Xenopus PPARγ ligands and determined the mechanism by which these chemicals bind to and activate PPARγ. We also found evidence that activation of ERα, ERβ, and PPARγ depends on the degree of halogenation in BPA analogs. We observed that the bulkier brominated BPA analogs, the greater their capability to activate PPARγ and the weaker their estrogenic potential. Conclusions: Our results strongly suggest that polyhalogenated bisphenols could function as obesogens by acting as agonists to disrupt physiological functions regulated by human or animal PPARγ. PMID:21561829

  15. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

    PubMed

    Patterson, Andrew D; Shah, Yatrik M; Matsubara, Tsutomu; Krausz, Kristopher W; Gonzalez, Frank J

    2012-07-01

    Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.

  16. Characterization of Paralichthys olivaceus peroxisome proliferator-activated receptor-α gene as a master regulator of flounder lipid metabolism.

    PubMed

    Cho, Hyun Kook; Kong, Hee Jeong; Kim, Hye Young; Cheong, JaeHun

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that play key roles in lipid and energy homeostasis. Paralichthys olivaceus PPARα (PoPPARα) cDNA was isolated by initial reverse transcription-polymerase chain reaction (RT-PCR) using conserved region among fish species and rapid amplification of cDNA ends (RACE). The full-length of PoPPARα cDNA is 2040-bp long encoding a polypeptide with 505 amino acids and containing a DNA binding domain (C4-type zinc finger) and a ligand-binding domain. PoPPARα was detected from 1 day post-hatch and was highly expressed in the stomach, liver, and intestine of continuously fed flounder, approximately 16 cm in size. PoPPARα mRNA expression was down-regulated in the kidney, stomach, and liver of the 4.5-month-old flounder after a 30 day food-deprivation period. PoPPARα activates the PPAR response element (PPRE)-driven reporter, and treatment with Wy14643, a PPARα agonist, augmented PoPPARα-stimulated peroxisome proliferator response element activity in HINAE and HepG2 cells. PoPPARα activated the expression of fatty acid β-oxidation related genes such as carnitine palmitoyltransferase 1A, medium chain acyl-CoA dehydrogenase, and acyl-CoA oxidase 1 and inhibited the expression of sterol regulatory element binding protein and fatty acid synthase by competitively inhibiting LXR/RXR heterodimer formation. These results suggest that PoPPARα plays an important role in lipid metabolism of olive flounder and that it is functionally and evolutionarily conserved in olive flounder and mammals. PMID:22051321

  17. Hypoxia induces peroxisome proliferator-activated receptor γ expression via HIF-1-dependent mechanisms in HepG2 cell line.

    PubMed

    Zhao, Ying-Ze; Liu, Xiao-Ling; Shen, Guo-Min; Ma, Yan-Ni; Zhang, Feng-Lin; Chen, Ming-Tai; Zhao, Hua-Lu; Yu, Jia; Zhang, Jun-Wu

    2014-02-01

    Hypoxia-inducible factor-1 (HIF-1) can activate expression of a broad range of genes in response to hypoxia. It has been shown that the levels of peroxisome proliferator-activated receptor γ (PPARγ) are influenced by changes in oxygen tension, and PPARγ plays a critical role in metabolism regulation and cancers. In this research, we observed an increased PPARγ mRNA and protein levels in company with increased HIF-1 protein levels in HepG2 cells in hypoxia as compared with in normoxia. Enforced expression of HIF-1α induced PPARγ1 and PPARγ2 expression, while knockdown of HIF-1α by small interference RNA deduced PPARγ1 and PPARγ2 expression in HepG2 cells under hypoxic conditions. By dual-luciferase reporter assay and chromatin immunoprecipitation assay we confirmed a functional hypoxic response element (HRE) localized at 684bp upstream of the transcriptional start site (TSS) of PPARγ1 and a functional HRE localized at 204bp downstream of the TSS of PPARγ2 in HepG2 cells. Additionally we observed an increase and co-presence of PPARγ and HIF-1α, and a highly positive correlation between PPARγ expression and HIF-1α expression (r=0.553, p<0.0001), in the same tumor tissue areas of hepatocellular carcinoma patients. Our data suggested a new mechanism of hepatocellular carcinoma cells response to hypoxia.

  18. A novel peroxisome proliferator-activated receptor alpha/gamma agonist, BPR1H0101, inhibits topoisomerase II catalytic activity in human cancer cells.

    PubMed

    Kao, Yu-Hsun; Hsieh, Hsing-Pang; Chitlimalla, Santhosh Kumar; Pan, Wen-Yu; Kuo, Ching-Chuan; Tsai, Yuan-Chin; Lin, Wen-Hsing; Chuang, Shuang-En; Chang, Jang-Yang

    2008-02-01

    Peroxisome proliferator-activated receptor (PPAR) gamma agonists are used clinically for treating diabetes mellitus and cancer. 2-Methyl-2[(1-{3-phenyl-7-propylbenzol[d]isoxazol-6-yl}oxy)propyl]-1H-4-indolyl) oxy]propanoic acid (BPR1H0101) is a novel synthetic indole-based compound, discovered through research to identify new PPARgamma agonists, and it acts as a dual agonist for PPARgamma and PPARalpha. Isobologram analysis demonstrated that BPR1H0101 is capable of antagonistic interaction with the topoisomerase (topo) II poison, VP16. A study of its mechanism showed that BPR1H0101 could inhibit the catalytic activity of topo II in vitro, but did not produce detectable topo II-mediated DNA strand breaks in human oral cancer KB cells. Furthermore, BPR1H0101 could inhibit VP16-induced topo II-mediated DNA cleavage and ataxia-telangiectasia-mutated phosphorylation in KB cells. The results suggest that BPR1H0101 can interfere with the topo II reaction by inhibiting catalytic activity before the formation of the intermediate cleavable complex; consequently, it can impede VP16-induced topo II-mediated DNA cleavage and cell death. This is the first identified PPARalpha/gamma agonist that can serve as a topo II catalytic inhibitor, to interfere with VP16-induced cell death. The result might have relevance to the clinical use of the PPARalpha/gamma agonist in combination chemotherapy. PMID:18176111

  19. Selenoprotein-dependent Up-regulation of Hematopoietic Prostaglandin D2 Synthase in Macrophages Is Mediated through the Activation of Peroxisome Proliferator-activated Receptor (PPAR) γ*

    PubMed Central

    Gandhi, Ujjawal H.; Kaushal, Naveen; Ravindra, Kodihalli C.; Hegde, Shailaja; Nelson, Shakira M.; Narayan, Vivek; Vunta, Hema; Paulson, Robert F.; Prabhu, K. Sandeep

    2011-01-01

    The plasticity of macrophages is evident from their dual role in inflammation and resolution of inflammation that are accompanied by changes in the transcriptome and metabolome. Along these lines, we have previously demonstrated that the micronutrient selenium increases macrophage production of arachidonic acid (AA)-derived anti-inflammatory 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and decreases the proinflammatory PGE2. Here, we hypothesized that selenium modulated the metabolism of AA by a differential regulation of various prostaglandin (PG) synthases favoring the production of PGD2 metabolites, Δ12-PGJ2 and 15d-PGJ2. A dose-dependent increase in the expression of hematopoietic-PGD2 synthase (H-PGDS) by selenium and a corresponding increase in Δ12-PGJ2 and 15d-PGJ2 in RAW264.7 macrophages and primary bone marrow-derived macrophages was observed. Studies with organic non-bioavailable forms of selenium and the genetic manipulation of cellular selenium incorporation machinery indicated that selenoproteins were necessary for H-PGDS expression and 15d-PGJ2 production. Treatment of selenium-deficient macrophages with rosiglitazone, a peroxisome proliferator-activated receptor γ ligand, up-regulated H-PGDS. Furthermore, electrophoretic mobility shift assays indicated the presence of an active peroxisome proliferator-activated receptor-response element in murine Hpgds promoter suggesting a positive feedback mechanism of H-PGDS expression. Alternatively, the expression of nuclear factor-κB-dependent thromboxane synthase and microsomal PGE2 synthase was down-regulated by selenium. Using a Friend virus infection model of murine leukemia, the onset of leukemia was observed only in selenium-deficient and indomethacin-treated selenium-supplemented mice but not in the selenium-supplemented group or those treated with 15d-PGJ2. These results suggest the importance of selenium in the shunting of AA metabolism toward the production of PGD2 metabolites, which may have

  20. Fibrates increase human apolipoprotein A-II expression through activation of the peroxisome proliferator-activated receptor.

    PubMed Central

    Vu-Dac, N; Schoonjans, K; Kosykh, V; Dallongeville, J; Fruchart, J C; Staels, B; Auwerx, J

    1995-01-01

    In view of the evidence linking plasma high density lipoprotein (HDL)-cholesterol levels to a protective effect against coronary artery disease and the widespread use of fibrates in the treatment of hyperlipidemia, the goal of this study was to analyze the influence of fibrates on the expression of apolipoprotein (apo) A-II, a major protein constituent of HDL. Administration of fenofibrate (300 mg/d) to 16 patients with coronary artery disease resulted in a marked increase in plasma apo A-II concentrations (0.34 +/- 0.11 to 0.45 +/- 0.17 grams/liter; P < 0.01). This increase in plasma apo A-II was due to a direct effect on hepatic apo A-II production, since fenofibric acid induced apo A-II mRNA levels to 450 and 250% of control levels in primary cultures of human hepatocytes and in human hepatoblastoma HepG2 cells respectively. The induction in apo A-II mRNA levels was followed by an increase in apo A-II secretion in both cell culture systems. Transient transfection experiments of a reporter construct driven by the human apo A-II gene promoter indicated that fenofibrate induced apo A-II gene expression at the transcriptional level. Furthermore, several other peroxisome proliferators, such as the fibrate, Wy-14643, and the fatty acid, eicosatetraynoic acid (ETYA), also induced apo A-II gene transcription. Unilateral deletions and site-directed mutagenesis identified a sequence element located in the J-site of the apo A-II promoter mediating the responsiveness to fibrates and fatty acids. This element contains two imperfect half sites spaced by 1 oligonucleotide similar to a peroxisome proliferator responsive element (PPRE). Cotransfection assays showed that the peroxisome proliferator activated receptor (PPAR) transactivates the apo A-II promoter through this AII-PPRE. Gel retardation assays demonstrated that PPAR binds to the AII-PPRE with an affinity comparable to its binding affinity to the acyl coA oxidase (ACO)-PPRE. In conclusion, in humans fibrates increase

  1. The discovery of novel isoflavone pan peroxisome proliferator-activated receptor agonists.

    PubMed

    Matin, Azadeh; Doddareddy, Munikumar Reddy; Gavande, Navnath; Nammi, Srinivas; Groundwater, Paul W; Roubin, Rebecca H; Hibbs, David E

    2013-02-01

    Twenty three dual PPARα and γ molecules of natural product origin, previously reported by our group, were further investigated for pan PPAR transactivation against PPARδ. The in vitro cell toxicity profile, as well as, in silico study of the most active molecules within this new class of pan PPAR agonists are also described. 3',5' Dimethoxy-7 hydroxyisoflavone 6, Ψ-baptigenin 7, 4' fluoro-7 hydroxyisoflavone 8, and 3' methoxy-7 hydroxyisoflavone 9 were identified as the most potent molecules studied within the set compared to the commercially available pan PPAR agonist, bezafibrate 1. These novel active molecules may thus be useful as future leads in PPAR-related disorders, including type II diabetes mellitus and metabolic syndrome. PMID:23265844

  2. Peroxisome proliferator-activated receptor {alpha} agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats

    SciTech Connect

    Chen Xiang; Li Ming; Sun Weiping; Bi Yan; Cai Mengyin; Liang Hua; Yu Qiuqiong; He Xiaoying; Weng Jianping

    2008-04-18

    It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11{beta}-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPAR{alpha}), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPAR{alpha} activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenofibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPAR{alpha} inhibitor MK886, suggesting that fenofibrate activated through PPAR{alpha}. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPAR{alpha}.

  3. Reactivation of peroxisome proliferator-activated receptor alpha is associated with contractile dysfunction in hypertrophied rat heart.

    PubMed

    Young, M E; Laws, F A; Goodwin, G W; Taegtmeyer, H

    2001-11-30

    In pressure overload-induced hypertrophy, the heart increases its reliance on glucose as a fuel while decreasing fatty acid oxidation. A key regulator of this substrate switching in the hypertrophied heart is peroxisome proliferator-activated receptor alpha (PPARalpha). We tested the hypothesis that down-regulation of PPARalpha is an essential component of cardiac hypertrophy at the levels of increased mass, gene expression, and metabolism by pharmacologically reactivating PPARalpha. Pressure overload (induced by constriction of the ascending aorta for 7 days in rats) resulted in cardiac hypertrophy, increased expression of fetal genes (atrial natriuretic factor and skeletal alpha-actin), decreased expression of PPARalpha and PPARalpha-regulated genes (medium chain acyl-CoA dehydrogenase and pyruvate dehydrogenase kinase 4), and caused substrate switching (measured ex vivo in the isolated working heart preparation). Treatment of rats with the specific PPARalpha agonist WY-14,643 (8 days) did not affect the trophic response or atrial natriuretic factor induction to pressure overload. However, PPARalpha activation blocked skeletal alpha-actin induction, reversed the down-regulation of measured PPARalpha-regulated genes in the hypertrophied heart, and prevented substrate switching. This PPARalpha reactivation concomitantly resulted in severe depression of cardiac power and efficiency in the hypertrophied heart (measured ex vivo). Thus, PPARalpha down-regulation is essential for the maintenance of contractile function of the hypertrophied heart. PMID:11574533

  4. Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction.

    PubMed

    Shin, Mi Hee; Lee, Se-Rah; Kim, Min-Kyoung; Shin, Chang-Yup; Lee, Dong Hun; Chung, Jin Ho

    2016-01-01

    Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging. PMID:27611371

  5. Rosiglitazone stimulates peroxisome proliferator-activated receptor gamma expression and directly affects in vitro steroidogenesis in porcine ovarian follicles.

    PubMed

    Rak-Mardyła, Agnieszka; Karpeta, Anna

    2014-07-01

    Rosiglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) synthetic activator from the group of thiazolidinediones often used in the treatment of chronic diseases such as type 2 diabetes and other forms of insulin resistance. The present in vitro study assessed the direct effects of rosiglitazone at 25 and 50 μM doses on PPARγ gene expression, steroid secretion (progesterone [P4], androstenedione [A4], testosterone [T], and estradiol), and protein expression of PPARγ, 3βHSD, CYP17, 17βHSD, CYP19 by porcine ovarian follicles from prepubertal and cycling animals. We analyzed also steroid enzymatic activity by conversion of pregnen-3β-ol-20-one to P4, P4 to A4, and A4 to T. Our results indicated that rosiglitazone increased significantly PPARγ expression, P4 secretion, 3βHSD activity, and protein expression. Rosiglitazone decreased A4 and T secretion by reducing the expression and activity of CYP17 and 17βHSD and did not change estradiol secretion and CYP19. Similarly results was observed both in prepubertal and cycling pigs. Our results indicate that these direct effects of rosiglitazone on ovarian steroidogenesis provide a framework for testing several potential new mechanisms of PPAR-γ actions on porcine ovarian function. PMID:24681211

  6. Computer-Aided Discovery, Validation, and Mechanistic Characterization of Novel Neolignan Activators of Peroxisome Proliferator-Activated Receptor γ

    PubMed Central

    Fakhrudin, Nanang; Ladurner, Angela; Atanasov, Atanas G.; Heiss, Elke H.; Baumgartner, Lisa; Markt, Patrick; Schuster, Daniela; Ellmerer, Ernst P.; Wolber, Gerhard; Rollinger, Judith M.; Stuppner, Hermann; Dirsch, Verena M.

    2012-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are used for the treatment of type 2 diabetes and metabolic syndrome. However, the currently used PPARγ agonists display serious side effects, which has led to a great interest in the discovery of novel ligands with favorable properties. The aim of our study was to identify new PPARγ agonists by a PPARγ pharmacophore–based virtual screening of 3D natural product libraries. This in silico approach led to the identification of several neolignans predicted to bind the receptor ligand binding domain (LBD). To confirm this prediction, the neolignans dieugenol, tetrahydrodieugenol, and magnolol were isolated from the respective natural source or synthesized and subsequently tested for PPARγ receptor binding. The neolignans bound to the PPARγ LBD with EC50 values in the nanomolar range, exhibiting a binding pattern highly similar to the clinically used agonist pioglitazone. In intact cells, dieugenol and tetrahydrodieugenol selectively activated human PPARγ-mediated, but not human PPARα- or -β/δ-mediated luciferase reporter expression, with a pattern suggesting partial PPARγ agonism. The coactivator recruitment study also demonstrated partial agonism of the tested neolignans. Dieugenol, tetrahydrodieugenol, and magnolol but not the structurally related eugenol induced 3T3-L1 preadipocyte differentiation, confirming effectiveness in a cell model with endogenous PPARγ expression. In conclusion, we identified neolignans as novel ligands for PPARγ, which exhibited interesting activation profiles, recommending them as potential pharmaceutical leads or dietary supplements. PMID:20064974

  7. PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?

    PubMed

    Feldman, P L; Lambert, M H; Henke, B R

    2008-01-01

    The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways. PMID:18537685

  8. Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo.

    PubMed

    Itami, A; Watanabe, G; Shimada, Y; Hashimoto, Y; Kawamura, J; Kato, M; Hosotani, R; Imamura, M

    2001-11-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPARgamma could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPARgamma is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPARgamma, troglitazone, led to G1 accumulation with the increase in p27(Kip1), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARgamma in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in part, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARgamma. Our results suggest that ligands of PPARgamma may be a novel therapeutic agent for the treatment of pancreatic carcinomas.

  9. 13-Oxo-9(Z),11(E),15(Z)-octadecatrienoic acid activates peroxisome proliferator-activated receptor γ in adipocytes.

    PubMed

    Takahashi, Haruya; Hara, Hideyuki; Goto, Tsuyoshi; Kamakari, Kosuke; Wataru, Nomura; Mohri, Shinsuke; Takahashi, Nobuyuki; Suzuki, Hideyuki; Shibata, Daisuke; Kawada, Teruo

    2015-01-01

    Peroxisome proliferator-activated receptor (PPAR)γ is expressed in adipose tissue and plays a key role in the regulation of adipogenesis. PPARγ activators are known to have potent antihyperglycemic activity and are used to treat insulin resistance associated with diabetes. Therefore, many natural and synthetic agonists of PPARγ are used in the treatment of glucose disorders. In the present study, we found that 13-oxo-9(Z),11(E),15(Z)-octadecatrienoic acid (13-oxo-OTA), a linolenic acid derivative, is present in the extract of tomato (Solanum lycopersicum), Mandarin orange (Citrus reticulata), and bitter gourd (Momordica charantia). We also found that 13-oxo-OTA activated PPARγ and induced the mRNA expression of PPARγ target genes in adipocytes, thereby promoting differentiation. Furthermore, 13-oxo-OTA induced secretion of adiponectin and stimulated glucose uptake in adipocytes. To our knowledge, this is the first study to report that 13-oxo-OTA induces adipogenesis through PPARγ activation and to present 13-oxo-OTA as a valuable food-derived compound that may be applied in the management of glucose metabolism disorders. PMID:25425149

  10. Impacts of peroxisome proliferator-activated receptor-γ activation on cigarette smoke-induced exacerbated response to bacteria.

    PubMed

    Morissette, Mathieu C; Shen, Pamela; Thayaparan, Danya; Stämpfli, Martin R

    2015-01-01

    Chronic obstructive pulmonary disease (COPD) is characterised by a state of chronic pulmonary inflammation punctuated by microbial exacerbations. Despite advances in treatment options, COPD remains difficult to manage. In this study, we investigated the potential of peroxisome proliferator-activated receptor (PPAR)γ activation as a new therapy against cigarette smoke-induced inflammation and its associated bacterial exacerbation. C57BL/6 mice were exposed to room air or cigarette smoke for either 4 days or 4 weeks and treated either prophylactically or therapeutically with rosiglitazone. The impact of rosiglitazone on cigarette smoke-induced exacerbated response to the bacterial pathogen nontypeable Haemophilus influenzae (NTHi) was studied using the therapeutic treatment protocol. We found that rosiglitazone was able to reduce cigarette smoke-induced neutrophilia both when administered prophylactically or therapeutically. Therapeutic intervention with rosiglitazone was also effective in preventing cigarette smoke-induced neutrophilia exacerbation following NTHi infection. Moreover, the anti-inflammatory effects of rosiglitazone did not lead to an increase in the pulmonary bacterial burden, unlike dexamethasone. Altogether, our data suggest that pharmacological activation of PPARγ may be an effective therapeutic approach to improve COPD management, as it is able to reduce cigarette smoke-induced inflammation and decrease the magnitude of bacterial exacerbations, without compromising the ability of the immune system to control the infection. PMID:25034559

  11. Chemical synthesis, docking studies and biological effects of a pan peroxisome proliferator-activated receptor agonist and cyclooxygenase inhibitor.

    PubMed

    Santin, José Roberto; Uchôa, Flávia D T; Lima, Maria do Carmo A; Rabello, Marcelo M; Machado, Isabel Daufenback; Hernandes, Marcelo Z; Amato, Angelica A; Milton, Flora Aparecida; Webb, Paul; Neves, Francisco de Assis Rocha; Galdino, Suely L; Pitta, Ivan Rocha; Farsky, Sandra H P

    2013-03-12

    The compound (5Z)-5-[(5-bromo-1H-indol-3-yl)methylene]-3-(4-chlorobenzyl)-thiazolidine-2,4-dione (LYSO-7) was synthesised in order to obtain a new type of anti-inflammatory drug, designed with hybrid features to inhibit cyclooxygenase (COX) and also to activate peroxisome proliferator-activated receptor (PPAR). Results obtained from docking (in silico) studies corroborated with experimental data, showing the potential affinity between the studied ligand and targets. The specificity of LYSO-7 for COX-enzymes was detected by the inhibition of COX-1 and COX-2 activities by 30% and 20%, respectively. In transactivation reporter gene assays LYSO-07 showed a pan partial agonist effect on the three PPAR subtypes (PPARγ, PPARα and PPARβ/δ). The agonist action on PPARγ was also observed by a pharmacological approach, as the reduction in the Escherichia coli lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1β) secretion and nitric oxide (NO) production by mouse neutrophils was blocked by GW9962, a specific PPARγ antagonist. Additionally, the in vivo effect was measured by reduced carrageenan-induced neutrophil influx into the subcutaneous tissue of mice. Taken together, these data show that LYSO-7 displays a potent in vivo anti-inflammatory effect during the innate acute response, which is dependent on its associated COX inhibitory activities and PPAR activation. PMID:23305993

  12. 9-Oxo-10(E),12(Z),15(Z)-Octadecatrienoic Acid Activates Peroxisome Proliferator-Activated Receptor α in Hepatocytes.

    PubMed

    Takahashi, Haruya; Kamakari, Kosuke; Goto, Tsuyoshi; Hara, Hideyuki; Mohri, Shinsuke; Suzuki, Hideyuki; Shibata, Daisuke; Nakata, Rieko; Inoue, Hiroyasu; Takahashi, Nobuyuki; Kawada, Teruo

    2015-11-01

    The peroxisome proliferator-activated receptor (PPAR)α is mainly expressed in the liver and plays an important role in the regulation of lipid metabolism. It has been reported that PPARα activation enhances fatty acid oxidation and reduces fat storage. Therefore, PPARα agonists are used to treat dyslipidemia. In the present study, we found that 9-oxo-10(E),12(Z),15(Z)-octadecatrienoic acid (9-oxo-OTA), which is a α-linolenic acid (ALA) derivative, is present in tomato (Solanum lycopersicum) extract. We showed that 9-oxo-OTA activated PPARα and induced the mRNA expression of PPARα target genes in murine primary hepatocytes. These effects promoted fatty acid uptake and the secretion of β-hydroxybutyrate, which is one of the endogenous ketone bodies. We also demonstrated that these effects of 9-oxo-OTA were not observed in PPARα-knockout (KO) primary hepatocytes. To our knowledge, this is the first study to report that 9-oxo-OTA promotes fatty acid metabolism via PPARα activation and discuss its potential as a valuable food-derived compound for use in the management of dyslipidemia. PMID:26387026

  13. Stimulation of proximal tubular cell apoptosis by albumin-bound fatty acids mediated by peroxisome proliferator activated receptor-gamma.

    PubMed

    Arici, Mustafa; Chana, Ravinder; Lewington, Andrew; Brown, Jez; Brunskill, Nigel John

    2003-01-01

    In nephrotic syndrome, large quantities of albumin enter the kidney tubule. This albumin carries with it a heavy load of fatty acids to which the proximal tubule cells are exposed at high concentration. It is postulated that exposure to fatty acids in this way is injurious to proximal tubule cells. This study has examined the ability of fatty acids to interact with peroxisome proliferator-activated receptors (PPAR) in primary cultures of human proximal tubule cells. Luciferase reporter assays in transiently transfected human proximal tubule cells were used to show that albumin bound fatty acids and other agonists activate PPARgamma in a dose-dependent manner. One of the consequences of this activation is apoptosis of the cells as determined by changes in cell morphology, evidence of PARP cleavage, and appearance of DNA laddering. Overexpression of PPARgamma in these cells also results in enhanced apoptosis. Both fatty acid-induced PPAR activation and apoptosis in these cells can be blocked by PPAR response element decoy oligonucleotides. Activation of PPARgamma by the specific agonist PGJ(2) is associated with inhibition of cell proliferation, whereas activation by albumin bound fatty acids is accompanied by increased proliferation. However, the net balance of apoptosis/proliferation favors deletion of cells. These results implicate albumin-bound fatty acids as important mediators of tubular injury in nephrosis and provide fresh impetus for pursuit of lipid-lowering strategies in proteinuric renal disease. PMID:12506134

  14. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists.

    PubMed

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD) and found that the ligand binding pocket (LBP) is occupied by bacterial medium chain fatty acids (MCFAs). We verified that MCFAs (C8-C10) bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5), linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD) simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H) 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H) 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  15. Role of peroxisome proliferator-activated receptor alpha and gamma in antiangiogenic effect of pomegranate peel extract

    PubMed Central

    Dana, Nasim; Javanmard, Shaghayegh Haghjooy; Rafiee, Laleh

    2016-01-01

    Objective(s): Herbal medicines are promising cancer preventive candidates. It has been shown that Punica granatum L. could inhibit angiogenesis and tumor invasion. In this study, we investigated whether the anti-angiogenic effect of pomegranate peel extract (PPE) is partly attributable to Peroxisome proliferator-activated receptors (PPARs) activation in the Human Umbilical Vein Endothelial Cells (HUVECs). Materials and Methods: Ethanol extract from PPE was prepared. HUVECs were treated in four groups (with PPE (10 μg/ml) alone, PPE with or without PPARγ (T0070907) and α (GW6471) antagonists, and control group). The possible effect of PPARs on angiogenic regulation was checked by Matrigel assay. The mRNA expression levels of vascular endothelial growth factor (VEGF) was detected by Quantitative reverse transcription-polymerase chain reaction (QRT-PCR). Results: PPE significantly inhibited both tube formation (size, length, and junction of tubes) and VEGF mRNA expression (P<0.05). Our results showed that the anti-angiogenic effects of PPE were significantly reversed by both PPAR antagonists (P<0.05). There was no difference between PPE plus antagonists groups and the control group. Conclusion: In summary our results showed that the anti-angiogenic effects of PPE could be mediated in part through PPAR dependent pathway. PMID:27096071

  16. Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes.

    PubMed

    Ribet, Carole; Montastier, Emilie; Valle, Carine; Bezaire, Véronic; Mazzucotelli, Anne; Mairal, Aline; Viguerie, Nathalie; Langin, Dominique

    2010-01-01

    This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPAR alpha and PPAR gamma actions in these cells. Primary cultures of human fat cells were treated with the PPAR alpha agonist GW7647 or the PPAR gamma agonist rosiglitazone. Changes in gene expression were determined using DNA microarrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of beta-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPAR alpha agonist. GW7647-induced alterations were abolished by a treatment with a PPAR alpha antagonist. Small interfering RNA-mediated extinction of PPAR alpha gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and beta-oxidation. Altogether these results show that PPAR alpha can selectively up-regulate beta-oxidation and decrease glucose utilization in human white adipocytes.

  17. Peroxisome proliferator-activated receptor-alpha control of lipid and glucose metabolism in human white adipocytes.

    PubMed

    Ribet, Carole; Montastier, Emilie; Valle, Carine; Bezaire, Véronic; Mazzucotelli, Anne; Mairal, Aline; Viguerie, Nathalie; Langin, Dominique

    2010-01-01

    This work aimed at characterizing the role of peroxisome proliferator-activated receptors (PPAR)alpha in human white adipocyte metabolism and at comparing PPAR alpha and PPAR gamma actions in these cells. Primary cultures of human fat cells were treated with the PPAR alpha agonist GW7647 or the PPAR gamma agonist rosiglitazone. Changes in gene expression were determined using DNA microarrays and quantitative RT-PCR. Western blot and metabolic studies were performed to identify the biological effects elicited by PPAR agonist treatments. GW7647 induced an up-regulation of beta-oxidation gene expression and increased palmitate oxidation. Unexpectedly, glycolysis was strongly reduced at transcriptional and functional levels by GW7647 leading to a decrease in pyruvate and lactate production. Glucose oxidation was decreased. Triglyceride esterification and de novo lipogenesis were inhibited by the PPAR alpha agonist. GW7647-induced alterations were abolished by a treatment with a PPAR alpha antagonist. Small interfering RNA-mediated extinction of PPAR alpha gene expression in hMADS adipocytes attenuated GW7647 induction of palmitate oxidation. Rosiglitazone had no major impact on glycolysis and beta-oxidation. Altogether these results show that PPAR alpha can selectively up-regulate beta-oxidation and decrease glucose utilization in human white adipocytes. PMID:19887568

  18. Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction

    PubMed Central

    Shin, Mi Hee; Lee, Se-Rah; Kim, Min-Kyoung; Shin, Chang-Yup

    2016-01-01

    Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging. PMID:27611371

  19. Zebrafish as a Model to Study the Role of Peroxisome Proliferating-Activated Receptors in Adipogenesis and Obesity

    PubMed Central

    Den Broeder, Marjo J.; Kopylova, Victoria A.; Kamminga, Leonie M.; Legler, Juliette

    2015-01-01

    The Peroxisome Proliferator-Activated Receptors (PPARs) PPARA and PPARD are regulators of lipid metabolism with important roles in energy release through lipid breakdown, while PPARG plays a key role in lipid storage and adipogenesis. The aim of this review is to describe the role of PPARs in lipid metabolism, adipogenesis, and obesity and evaluate the zebrafish as an emerging vertebrate model to study the function of PPARs. Zebrafish are an appropriate model to study human diseases, including obesity and related metabolic diseases, as pathways important for adipogenesis and lipid metabolism which are conserved between mammals and fish. This review synthesizes knowledge on the role of PPARs in zebrafish and focuses on the putative function of PPARs in zebrafish adipogenesis. Using in silico analysis, we confirm the presence of five PPARs (pparaa, pparab, pparda, ppardb, and pparg) in the zebrafish genome with 67–74% identity to human and mouse PPARs. During development, pparda/b paralogs and pparg show mRNA expression around the swim bladder and pancreas, the region where adipocytes first develop, whereas pparg is detectable in adipocytes at 15 days post fertilization (dpf). This review indicates that the zebrafish is a promising model to investigate the specific functions of PPARs in adipogenesis and obesity. PMID:26697060

  20. Activators of peroxisome proliferator-activated receptor gamma have depot-specific effects on human preadipocyte differentiation.

    PubMed Central

    Adams, M; Montague, C T; Prins, J B; Holder, J C; Smith, S A; Sanders, L; Digby, J E; Sewter, C P; Lazar, M A; Chatterjee, V K; O'Rahilly, S

    1997-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR) gamma, a nuclear receptor highly expressed in adipocytes, induces the differentiation of murine preadipocyte cell lines. Recently, thiazolidinediones (TZDs), a novel class of insulin-sensitizing compounds effective in the treatment of non-insulin-dependent diabetes mellitus (NIDDM) have been shown to bind to PPARgamma with high affinity. We have examined the effects of these compounds on the differentiation of human preadipocytes derived from subcutaneous (SC) and omental (Om) fat. Assessed by lipid accumulation, glycerol 3-phosphate dehydrogenase activity, and mRNA levels, subcultured preadipocytes isolated from either SC or Om depots did not differentiate in defined serum-free medium. Addition of TZDs (BRL49653 or troglitazone) or 15-deoxyDelta12,14prostaglandin J2 (a natural PPARgamma ligand) enhanced markedly the differentiation of preadipocytes from SC sites, assessed by all three criteria. The rank order of potency of these agents in inducing differentiation matched their ability to activate transcription via human PPARgamma. In contrast, preadipocytes from Om sites in the same individuals were refractory to TZDs, although PPARgamma was expressed at similar levels in both depots. The mechanism of this depot-specific TZD response is unknown. However, given the association between Om adiposity and NIDDM, the site-specific responsiveness of human preadipocytes to TZDs may be involved in the beneficial effects of these compounds on in vivo insulin sensitivity. PMID:9399962

  1. Coactivation of the human vitamin D receptor by the peroxisome proliferator-activated receptor gamma coactivator-1 alpha.

    PubMed

    Savkur, Rajesh S; Bramlett, Kelli S; Stayrook, Keith R; Nagpal, Sunil; Burris, Thomas P

    2005-08-01

    The vitamin D receptor (VDR) belongs to the superfamily of steroid/thyroid hormone receptors that is activated by 1alpha,25-dihydroxyvitamin D(3). Traditional targets for 1alpha,25-dihydroxyvitamin D(3) action include tissues involved in the maintenance of calcium homeostasis and bone development and remodeling. Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha), a transcriptional coactivator that plays a role in mitochondrial biogenesis and energy metabolism, is predominantly expressed in kidney, heart, liver, and skeletal muscle. Because VDR and PGC-1alpha display an overlapping pattern of expression, we investigated the possibility that PGC-1alpha could serve as a coactivator for VDR. Transient cotransfection assays demonstrate that PGC-1alpha augments ligand-dependent VDR transcription when either full-length VDR or Gal4 DNA binding domain-VDR-ligand binding domain chimeras were analyzed. Furthermore, mammalian two-hybrid assays, coimmunoprecipitation analyses, and biochemical coactivator recruitment assays demonstrate a ligand-dependent interaction between the two proteins both in cells and in vitro. The coactivation potential of PGC-1alpha requires an intact AF-2 domain of VDR and the LXXLL motif in PGC-1alpha. Taken together, these results indicate that PGC-1alpha serves as a coactivator for VDR.

  2. Prenatal Polycyclic Aromatic Hydrocarbon, Adiposity, Peroxisome Proliferator-Activated Receptor (PPAR) γ Methylation in Offspring, Grand-Offspring Mice

    PubMed Central

    Yan, Zhonghai; Zhang, Hanjie; Maher, Christina; Arteaga-Solis, Emilio; Champagne, Frances A.; Wu, Licheng; McDonald, Jacob D.; Yan, Beizhan; Schwartz, Gary J.; Miller, Rachel L.

    2014-01-01

    Rationale Greater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH) have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear. Objectives We hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected. Materials and Methods Pregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND) 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer-binding proteins (C/EBP) α, cyclooxygenase (Cox)-2, fatty acid synthase (FAS) and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue. Findings Offspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice. Conclusions Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny. PMID:25347678

  3. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma.

    PubMed

    Nagatomo, Akifumi; Nishida, Norihisa; Matsuura, Yoichi; Shibata, Nobuhito

    2013-06-01

    Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARγ expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT.

  4. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma

    PubMed Central

    Nagatomo, Akifumi; Nishida, Norihisa; Matsuura, Yoichi; Shibata, Nobuhito

    2013-01-01

    Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARγ expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT. PMID:24471115

  5. Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma

    PubMed Central

    Hsu, Hui-Tzu; Sung, Ming-Ta; Lee, Chih-Chun; Kuo, Yin-Ju; Chi, Chin-Wen; Lee, Hsin-Chen; Hsia, Cheng-Yuan

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC) remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006), and exhibited more tumor numbers (p = 0.038), more macroscopic vascular invasion (MVI) (p = 0.008), and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis) stages at diagnosis (p = 0.013) than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients. PMID:27483249

  6. Cell-Specific Determinants of Peroxisome Proliferator-Activated Receptor γ Function in Adipocytes and Macrophages ▿ §

    PubMed Central

    Lefterova, Martina I.; Steger, David J.; Zhuo, David; Qatanani, Mohammed; Mullican, Shannon E.; Tuteja, Geetu; Manduchi, Elisabetta; Grant, Gregory R.; Lazar, Mitchell A.

    2010-01-01

    The nuclear receptor peroxisome proliferator activator receptor γ (PPARγ) is the target of antidiabetic thiazolidinedione drugs, which improve insulin resistance but have side effects that limit widespread use. PPARγ is required for adipocyte differentiation, but it is also expressed in other cell types, notably macrophages, where it influences atherosclerosis, insulin resistance, and inflammation. A central question is whether PPARγ binding in macrophages occurs at genomic locations the same as or different from those in adipocytes. Here, utilizing chromatin immunoprecipitation and high-throughput sequencing (ChIP-seq), we demonstrate that PPARγ cistromes in mouse adipocytes and macrophages are predominantly cell type specific. In thioglycolate-elicited macrophages, PPARγ colocalizes with the hematopoietic transcription factor PU.1 in areas of open chromatin and histone acetylation, near a distinct set of immune genes in addition to a number of metabolic genes shared with adipocytes. In adipocytes, the macrophage-unique binding regions are marked with repressive histone modifications, typically associated with local chromatin compaction and gene silencing. PPARγ, when introduced into preadipocytes, bound only to regions depleted of repressive histone modifications, where it increased DNA accessibility, enhanced histone acetylation, and induced gene expression. Thus, the cell specificity of PPARγ function is regulated by cell-specific transcription factors, chromatin accessibility, and histone marks. Our data support the existence of an epigenomic hierarchy in which PPARγ binding to cell-specific sites not marked by repressive marks opens chromatin and leads to local activation marks, including histone acetylation. PMID:20176806

  7. Peroxisome proliferator-activated receptorα agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.

    PubMed

    González, María Del Carmen; Corton, J Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Alvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

    2012-01-01

    Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

  8. Peroxisome Proliferator-Activated Receptorα Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells

    PubMed Central

    González, María del Carmen; Corton, J. Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Álvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

    2012-01-01

    Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans. PMID:22701468

  9. Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice.

    PubMed

    Balandaram, Gayathri; Kramer, Lance R; Kang, Boo-Hyon; Murray, Iain A; Perdew, Gary H; Gonzalez, Frank J; Peters, Jeffrey M

    2016-07-01

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPARβ/δ in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPARβ/δ in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPARβ/δ in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPARβ/δ inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Pparβ/δ-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPARβ/δ compared to controls. Combined, these results suggest that ligand activation of PPARβ/δ attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells. PMID:27427494

  10. Identification of isosilybin a from milk thistle seeds as an agonist of peroxisome proliferator-activated receptor gamma.

    PubMed

    Pferschy-Wenzig, Eva-Maria; Atanasov, Atanas G; Malainer, Clemens; Noha, Stefan M; Kunert, Olaf; Schuster, Daniela; Heiss, Elke H; Oberlies, Nicholas H; Wagner, Hildebert; Bauer, Rudolf; Dirsch, Verena M

    2014-04-25

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism. Agonists of this nuclear receptor are used in the treatment of type 2 diabetes and are also studied as a potential treatment of other metabolic diseases, including nonalcoholic fatty liver disease. Silymarin, a concentrated phenolic mixture from milk thistle (Silybum marianum) seeds, is used widely as a supportive agent in the treatment of a variety of liver diseases. In this study, the PPARγ activation potential of silymarin and its main constituents was investigated. Isosilybin A (3) caused transactivation of a PPARγ-dependent luciferase reporter in a concentration-dependent manner. This effect could be reversed upon co-treatment with the PPARγ antagonist T0070907. In silico docking studies suggested a binding mode for 3 distinct from that of the inactive silymarin constituents, with one additional hydrogen bond to Ser342 in the entrance region of the ligand-binding domain of the receptor. Hence, isosilybin A (3) has been identified as the first flavonolignan PPARγ agonist, suggesting its further investigation as a modulator of this nuclear receptor.

  11. Multiple Interactions between Peroxisome Proliferators-Activated Receptors and the Ubiquitin-Proteasome System and Implications for Cancer Pathogenesis

    PubMed Central

    Genini, Davide; Carbone, Giuseppina M.; Catapano, Carlo V.

    2008-01-01

    The peroxisome proliferator-activated receptors (PPAR) α, β/δ, and γ are ligand-activated nuclear receptors involved in a number of physiological processes, including lipid and glucose homeostasis, inflammation, cell growth, differentiation, and death. PPAR agonists are used in the treatment of human diseases, like type 2 diabetes and dyslipidemia, and PPARs appear as promising therapeutic targets in other conditions, including cancer. A better understanding of the functions and regulation of PPARs in normal and pathological processes is of primary importance to devise appropriate therapeutic strategies. The ubiquitin-proteasome system (UPS) plays an important role in controlling level and activity of many nuclear receptors and transcription factors. PPARs are subjected to UPS-dependent regulation. Interestingly, the three PPAR isotypes are differentially regulated by the UPS in response to ligand-dependent activation, a phenomenon that may be intrinsically connected to their distinct cellular functions and behaviors. In addition to their effects ongene expression, PPARs appear to affect protein levels and downstream pathways also by modulating the activity of the UPS in target-specific manners. Here we review the current knowledge of the interactions between the UPS and PPARs in light of the potential implications for their effects on cell fate and tumorigenesis. PMID:18551186

  12. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-{gamma} ligand, rosiglitazone

    SciTech Connect

    Wakui, Yuta; Inoue, Jun; Ueno, Yoshiyuki; Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru

    2010-05-28

    Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-{alpha}, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPAR{alpha} ligand, bezafibrate, and a PPAR{gamma} ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPAR{gamma}, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-{alpha}-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

  13. Adiponectin, a downstream target gene of peroxisome proliferator-activated receptor {gamma}, controls hepatitis B virus replication

    SciTech Connect

    Yoon, Sarah; Jung, Jaesung; Kim, Taeyeung; Park, Sun; Chwae, Yong-Joon; Shin, Ho-Joon; Kim, Kyongmin

    2011-01-20

    In this study, HepG2-hepatitis B virus (HBV)-stable cells that did not overexpress HBx and HBx-deficient mutant-transfected cells were analyzed for their expression of HBV-induced, upregulated adipogenic and lipogenic genes. The mRNAs of CCAAT enhancer binding protein {alpha} (C/EBP{alpha}), peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), adiponectin, liver X receptor {alpha} (LXR{alpha}), sterol regulatory element binding protein 1c (SREBP1c), and fatty acid synthase (FAS) were expressed at higher levels in HepG2-HBV and lamivudine-treated stable cells and HBx-deficient mutant-transfected cells than in the HepG2 cells. Lamivudine treatment reduced the mRNA levels of PPAR{gamma} and C/EBP{alpha}. Conversely, HBV replication was upregulated by adiponectin and PPAR{gamma} agonist rosiglitazone treatments and was downregulated by adiponectin siRNAs. Collectively, our results demonstrate that HBV replication and/or protein expression, even in the absence of HBx, upregulated adipogenic or lipogenic genes, and that the control of adiponectin might prove useful as a therapeutic modality for the treatment of chronic hepatitis B.

  14. Peroxisome proliferator-activated receptor gamma agonists in the prevention and treatment of murine systemic lupus erythematosus

    PubMed Central

    Aprahamian, Tamar R; Bonegio, Ramon G; Weitzner, Zachary; Gharakhanian, Raffi; Rifkin, Ian R

    2014-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) agonists are known to have many immunomodulatory effects. We have previously shown that the PPARγ agonist rosiglitazone is beneficial when used early in prevention of disease in murine models of systemic lupus erythematosus (SLE) and SLE-related atherosclerosis. In this report, we demonstrate that another PPARγ agonist, pioglitazone is also beneficial as a treatment for early murine lupus, indicating that this is a class effect and not agent-specific. We further attempt to define the ability of PPARγ agonists to ameliorate established or severe autoimmune disease using two mouse models: the MRL.lpr SLE model and the gld.apoE−/− model of accelerated atherosclerosis and SLE. We demonstrate that, in contrast to the marked amelioration of disease seen when PPARγ agonist treatment was started before disease onset, treatment with rosiglitazone after disease onset in MRL.lpr or gld.apoE−/− mice had minimal beneficial effect on the development of the autoimmune phenotype; however, rosiglitazone treatment remained highly effective at reducing lupus-associated atherosclerosis in gld.apoE−/− mice after disease onset or when mice were maintained on a high cholesterol Western diet. These results suggest that beneficial effects of PPARγ agonists on the development of autoimmunity might be limited to the early stages of disease, but that atherosclerosis, a major cause of death in SLE patients, may be ameliorated even in established or severe disease. PMID:24456224

  15. Peroxisome-proliferator-activated receptor-{gamma} agonists inhibit the release of proinflammatory cytokines from RSV-infected epithelial cells

    SciTech Connect

    Arnold, Ralf . E-mail: ralf.arnold@medizin.uni-magdeburg.de; Koenig, Wolfgang

    2006-03-15

    The epithelial cells of the airways are the target cells for respiratory syncytial virus (RSV) infection and the site of the majority of the inflammation associated with the disease. Recently, peroxisome-proliferator-activated receptor {gamma} (PPAR{gamma}), a member of the nuclear hormone receptor superfamily, has been shown to possess anti-inflammatory properties. Therefore, we investigated the role of PPAR{gamma} agonists (15d-PGJ{sub 2}, ciglitazone and troglitazone) on the synthesis of RSV-induced cytokine release from RSV-infected human lung epithelial cells (A549). We observed that all PPAR{gamma} ligands inhibited dose-dependently the release of TNF-{alpha}, GM-CSF, IL-1{alpha}, IL-6 and the chemokines CXCL8 (IL-8) and CCL5 (RANTES) from RSV-infected A549 cells. Concomitantly, the PPAR{gamma} ligands diminished the cellular amount of mRNA encoding for IL-6, CXCL8 and CCL5 and the RSV-induced binding activity of the transcription factors NF-{kappa}B (p65/p50) and AP-1 (c-fos), respectively. Our data presented herein suggest a potential application of PPAR{gamma} ligands in the anti-inflammatory treatment of RSV infection.

  16. Differential effects of triclosan on the activation of mouse and human peroxisome proliferator-activated receptor alpha.

    PubMed

    Wu, Yuanfeng; Wu, Qiangen; Beland, Frederick A; Ge, Peter; Manjanatha, Mugimane G; Fang, Jia-Long

    2014-11-18

    Triclosan is an anti-bacterial agent used in many personal care products, household items, medical devices, and clinical settings. Liver tumors occur in mice exposed to triclosan, a response attributed to peroxisome proliferator-activated receptor alpha (PPARα) activation; however, the effects of triclosan on mouse and human PPARα have not been fully evaluated. We compared the effects of triclosan on mouse and human PPARα using PPARα reporter assays and on downstream events of PPARα activation using mouse hepatoma Hepa1c1c7 cells and human hepatoma HepG2 cells. PPARα transcriptional activity was increased by triclosan in a mouse PPARα reporter assay and decreased in a human PPARα reporter assay. Concentrations of triclosan inhibiting 50% cell growth were similar in both human and mouse hepatoma cells. Western blotting analysis showed that triclosan increased acyl-coenzyme A oxidase (ACOX1), a PPARα target, in Hepa1c1c7 cells but decreased the level in HepG2 cells. Treatment of Hepa1c1c7 cells with triclosan enhanced DNA synthesis and suppressed transforming growth factor beta-mediated apoptosis. This did not occur in HepG2 cells. These data demonstrate that triclosan had similar cytotoxicity in Hepa1c1c7 and HepG2 cells, but differential effects on the activation of PPARα, the expression of ACOX1, and downstream events including DNA synthesis and apoptosis.

  17. Peroxisome proliferator-activated receptor gamma (PPARγ) in brown trout: Interference of estrogenic and androgenic inputs in primary hepatocytes.

    PubMed

    Lopes, Célia; Madureira, Tânia Vieira; Ferreira, Nádia; Pinheiro, Ivone; Castro, L Filipe C; Rocha, Eduardo

    2016-09-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a pivotal regulator of lipid and glucose metabolism in vertebrates. Here, we isolated and characterized for the first time the PPARγ gene from brown trout (Salmo trutta f. fario). Hormones have been reported to interfere with the regulatory function of PPARγ in various organisms, albeit with little focus on fish. Thus, primary hepatocytes isolated from juveniles of brown trout were exposed to 1, 10 and 50μM of ethinylestradiol (EE2) or testosterone (T). A significant (3 fold) decrease was obtained in response to 50μM of EE2 and to 10 and 50μM of T (13 and 14 folds), while a 3 fold increase was observed at 1μM of EE2. Therefore, trout PPARγ seems a target for natural/synthetic compounds with estrogenic or androgenic properties and so, we advocate considering PPARγ as another alert sensor gene when assessing the effects of sex-steroid endocrine disruptors. PMID:27541269

  18. Peroxisome proliferator-activated receptor gamma ligands induce growth inhibition and apoptosis of human B lymphocytic leukemia.

    PubMed

    Zang, Chuanbing; Liu, Hongyu; Posch, Maximilian G; Waechter, Maries; Facklam, Margit; Fenner, Martin H; Ruthardt, Martin; Possinger, Kurt; Phillip Koeffler, H; Elstner, Elena

    2004-04-01

    This study examined the expression and structural intactness of peroxisome proliferator-activated receptor gamma (PPARgamma) in human acute lymphocytic leukemia (ALL) cells and determined the effect of PPARgamma ligands on growth and apoptosis of these cells. We noted that all lymphocytic leukemia cell lines expressed PPARgamma and no PPARgamma mutations were found in these cell lines as indicated by SSCP analysis. Effect of the PPARgamma ligands on the proliferation, differentiation and apoptosis of B type ALL cells was further examined. Treatment of these cells with the PPARgamma ligands Pioglitazone (PGZ) and 15-deoxy-delta (12,14)-prostaglandin J2 (15d-PGJ2) resulted in growth inhibition in a dose-dependent manner which was associated with a G1 to S cell cycle arrest. However, this effect appeared to be PPARgamma-independent since several PPARgamma antagonists could not reverse this effect. No differentiation was induced by this treatment. Four out of five cell lines underwent apoptosis after culture with the PPARgamma ligands. This effect was partially caspase-dependent because a pan-caspase inhibitor partially reversed this effect. In conclusion, our results suggest that PPARgamma ligands may offer a new therapeutic approach to aid in the treatment of ALL. PMID:15109539

  19. Peroxisome proliferator-activated receptor-gamma calls for activation in moderation: lessons from genetics and pharmacology.

    PubMed

    Knouff, Chris; Auwerx, Johan

    2004-12-01

    The peroxisome proliferator-activated receptor gamma (PPARgamma) is a prototypical member of the nuclear receptor superfamily and integrates the control of energy, lipid, and glucose homeostasis. PPARgamma can bind a variety of small lipophilic compounds derived from metabolism and nutrition. These ligands, in turn, determine cofactor recruitment to PPARgamma, regulating the transcription of genes in a variety of metabolic pathways. PPARgamma is the main target of the thiazolidinedione class of insulin-sensitizing drugs, which are currently a mainstay of therapy for type 2 diabetes. However, this therapy has a number of side effects. Here, we review the clinical consequences of PPARgamma polymorphisms in humans, as well as several studies in mice using general or tissue-specific knockout techniques. We also discuss the recent pharmacological literature describing a variety of new PPARgamma partial agonists and antagonists, as well as pan-PPAR agonists. The results of these studies have added to the understanding of PPARgamma function, allowing us to hypothesize a general mechanism of PPARgamma action and speculate on future trends in the use of PPARgamma as a target in the treatment of type II diabetes. PMID:15583022

  20. Ligand-Activated Peroxisome Proliferator-activated Receptor β/δ Modulates Human Endometrial Cancer Cell Survival

    PubMed Central

    MA, JJ; Monsivais, D; Dyson, MT; Coon, JS; Malpani, S; Ono, M; Zhao, H; Xin, H; Pavone, ME; Kim, JJ; Chakravarti, D; Bulun, SE

    2013-01-01

    Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity- contributing to approximately 8,200 annual deaths in the United States. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study we examined the contribution of the peroxisome proliferator-activated receptor β/δ (PPARβ/δ) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARβ/δ agonists, GW0742 and GW501516, PPARβ/δ inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARβ/δ-induced effects on cell proliferation and apoptosis was demonstrated using PPARβ/δ-selective antagonists and PPARβ/δ siRNA in combination with PPARβ/δ-selective agonists. Furthermore, we showed that PPARβ/δ activation increased PTEN expression, which led to AKT and GSK3β dephosphorylation, and increased β-catenin phosphorylation associated with its degradation. Overall, our data suggest that the anti-tumorigenic effect of PPARβ/δ activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3β/β-catenin pathway. These findings warrant further investigation of PPARβ/δ as a therapeutic target in endometrial cancer. PMID:23943160

  1. Transgenic expression of proximal tubule peroxisome proliferator-activated receptor-alpha in mice confers protection during acute kidney injury.

    PubMed

    Li, Shenyang; Nagothu, Kiran K; Desai, Varsha; Lee, Taewon; Branham, William; Moland, Carrie; Megyesi, Judit K; Crew, Mark D; Portilla, Didier

    2009-11-01

    Our previous studies suggest that peroxisome proliferator-activated receptor-alpha (PPARalpha) plays a critical role in regulating fatty acid beta-oxidation in kidney tissue and this directly correlated with preservation of kidney morphology and function during acute kidney injury. To further study this, we generated transgenic mice expressing PPARalpha in the proximal tubule under the control of the promoter of KAP2 (kidney androgen-regulated protein 2). Segment-specific upregulation of PPARalpha expression by testosterone treatment of female transgenic mice improved kidney function during cisplatin or ischemia-reperfusion-induced acute kidney injury. Ischemia-reperfusion injury or treatment with cisplatin in wild-type mice caused inhibition of fatty-acid oxidation, reduction of mitochondrial genes of oxidative phosphorylation, mitochondrial DNA, fatty-acid metabolism, and the tricarboxylic acid cycle. Similar injury in testosterone-treated transgenic mice resulted in amelioration of these effects. Similarly, there were increases in the levels of 4-hydroxy-2-hexenal-derived lipid peroxidation products in wild-type mice, which were also reduced in the transgenic mice. Similarly, necrosis of the S3 segment was reduced in the two injury models in transgenic mice compared to wild type. Our results suggest proximal tubule PPARalpha activity serves as a metabolic sensor. Its increased expression without the use of an exogenous PPARalpha ligand in the transgenic mice is sufficient to protect kidney function and morphology, and to prevent abnormalities in lipid metabolism associated with acute kidney injury.

  2. Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice.

    PubMed

    Balandaram, Gayathri; Kramer, Lance R; Kang, Boo-Hyon; Murray, Iain A; Perdew, Gary H; Gonzalez, Frank J; Peters, Jeffrey M

    2016-07-01

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPARβ/δ in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPARβ/δ in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPARβ/δ in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPARβ/δ inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Pparβ/δ-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPARβ/δ compared to controls. Combined, these results suggest that ligand activation of PPARβ/δ attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells.

  3. Decreased peroxisome proliferator-activated receptor γ level and signalling in sebaceous glands of patients with acne vulgaris.

    PubMed

    Dozsa, A; Mihaly, J; Dezso, B; Csizmadia, E; Keresztessy, T; Marko, L; Rühl, R; Remenyik, E; Nagy, L

    2016-07-01

    Little is known about the altered lipid metabolism-related transcriptional events occuring in sebaceous glands of patients with acne vulgaris. Peroxisome proliferator-activated receptor (PPAR)γ, a lipid-activated transcription factor, is implicated in differentiation and lipid metabolism of sebocytes. We have observed that PPARγ and its target genes, ADRP (adipose differentiation related protein) and PGAR (PPARγ angioprotein related protein) are expressed at lower levels in sebocytes from patients with acne than in those from healthy controls (HCs) Furthermore, endogenous PPARγ activator lipids such as arachidonic acid-derived keto-metabolites (e.g. 5KETE, 12KETE) are increased in acne-involved and nonacne-involved skin of patients with acne, compared with skin from healthy individuals. Our findings highlight the possible anti-inflammatory role of endogenous ligand-activated PPARγ signaling in human sebocyte biology, and suggest that modulating PPARγ- expression and thereby signaling might be a promising strategy for the clinical management of acne vulgaris.

  4. SDP1 is a peroxisome-proliferator-activated receptor gamma 2 co-activator that binds through its SCAN domain.

    PubMed Central

    Babb, Robert; Bowen, Benjamin R

    2003-01-01

    Peroxisome-proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, play an important role in the regulation of lipid metabolism and energy homoeostasis. In a yeast two-hybrid experiment using the zinc-finger transcription factor ZNF202 as bait, we previously identified the SCAN-domain-containing protein SDP1. SDP1 shares a high degree of amino acid sequence identity with PGC-2, a previously identified PPAR gamma 2 co-activator from the mouse. Here we show that SDP1 and PGC-2 interact with PPAR gamma 2 through their SCAN domains, even though PPAR gamma 2 does not contain a SCAN domain. Similar to PGC-2, SDP1 enhanced PPAR gamma 2-dependent gene transcription in transiently transfected cells but did not alter the affinity of PPAR gamma 2 for agonists. Although the SCAN domain was necessary for binding to PPAR gamma 2, it was not sufficient for co-activation in cells, suggesting that other features of SDP1 are responsible for transcriptional co-activation. The ability of SDP1 to interact with two different transcription factors that regulate genes involved in lipid metabolism, ZNF202 and PPAR gamma 2, suggests that SDP1 may be an important co-regulator of such genes. PMID:12444922

  5. IL-4 inhibits osteoclast formation through a direct action on osteoclast precursors via peroxisome proliferator-activated receptor γ1

    PubMed Central

    Bendixen, Amy C.; Shevde, Nirupama K.; Dienger, Krista M.; Willson, Timothy M.; Funk, Colin D.; Pike, J. Wesley

    2001-01-01

    IL-4 is a pleiotropic immune cytokine secreted by activated TH2 cells that inhibits bone resorption both in vitro and in vivo. The cellular targets of IL-4 action as well as its intracellular mechanism of action remain to be determined. We show here that IL-4 inhibits receptor activator of NF-κB ligand-induced osteoclast differentiation through an action on osteoclast precursors that is independent of stromal cells. Interestingly, this inhibitory effect can be mimicked by both natural as well as synthetic peroxisome proliferator-activated receptor γ1 (PPARγ1) ligands and can be blocked by the irreversible PPARγ antagonist GW 9662. These findings suggest that the actions of IL-4 on osteoclast differentiation are mediated by PPARγ1, an interpretation strengthened by the observation that IL-4 can activate a PPARγ1-sensitive luciferase reporter gene in RAW264.7 cells. We also show that inhibitors of enzymes such as 12/15-lipoxygenase and the cyclooxygenases that produce known PPARγ1 ligands do not abrogate the IL-4 effect. These findings, together with the observation that bone marrow cells from 12/15-lipoxygenase-deficient mice retain sensitivity to IL-4, suggest that the cytokine may induce novel PPARγ1 ligands. Our results reveal that PPARγ1 plays an important role in the suppression of osteoclast formation by IL-4 and may explain the beneficial effects of the thiazolidinedione class of PPARγ1 ligands on bone loss in diabetic patients. PMID:11226258

  6. Genetic interference with peroxisome proliferator-activated receptor γ in smooth muscle enhances myogenic tone in the cerebrovasculature via A Rho kinase-dependent mechanism.

    PubMed

    De Silva, T Michael; Ketsawatsomkron, Pimonrat; Pelham, Christopher; Sigmund, Curt D; Faraci, Frank M

    2015-02-01

    Myogenic responses by resistance vessels are a key component of autoregulation in brain, thus playing a crucial role in regulating cerebral blood flow and protecting the blood-brain barrier against potentially detrimental elevations in blood pressure. Although cerebrovascular disease is often accompanied by alterations in myogenic responses, mechanisms that control these changes are poorly understood. Peroxisome proliferator-activated receptor γ has emerged as a regulator of vascular tone. We hypothesized that interference with peroxisome proliferator-activated receptor γ in smooth muscle would augment myogenic responses in cerebral arteries. We studied transgenic mice expressing a dominant-negative mutation in peroxisome proliferator-activated receptor γ selectively in smooth muscle (S-P467L) and nontransgenic littermates. Myogenic tone in middle cerebral arteries from S-P467L was elevated 3-fold when compared with nontransgenic littermates. Rho kinase is thought to play a major role in cerebrovascular disease. The Rho kinase inhibitor, Y-27632, abolished augmented myogenic tone in middle cerebral arteries from S-P467L mice. CN-03, which modifies RhoA making it constitutively active, elevated myogenic tone to ≈60% in both strains, via a Y-27632-dependent mechanism. Large conductance Ca(2+)-activated K(+) channels (BKCa) modulate myogenic tone. Inhibitors of BKCa caused greater constriction in middle cerebral arteries from nontransgenic littermates when compared with S-P467L. Expression of RhoA or Rho kinase-I/II protein was similar in cerebral arteries from S-P467L mice. Overall, the data suggest that peroxisome proliferator-activated receptor γ in smooth muscle normally inhibits Rho kinase and promotes BKCa function, thus influencing myogenic tone in resistance arteries in brain. These findings have implications for mechanisms that underlie large- and small-vessel disease in brain, as well as regulation of cerebral blood flow. PMID:25385762

  7. Effect-Directed Analysis of Human Peroxisome Proliferator-Activated Nuclear Receptors (PPARγ1) Ligands in Indoor Dust.

    PubMed

    Fang, Mingliang; Webster, Thomas F; Stapleton, Heather M

    2015-08-18

    Agonism of human peroxisome proliferator-activated nuclear receptor gamma (PPARγ1) was recently observed in 15 of 25 samples of indoor dust extracts at environmentally relevant exposure levels. In this study, an effect-directed analysis approach was used to identify the primary contributors of PPARγ1 activity in the dust extracts. Three dust extracts showing significant PPARγ1 activity were fractionated with normal phase high-performance liquid chromatography (NP-HPLC) and each fraction was tested for PPARγ1 activity. Three dust extracts showed a similar PPARγ1 activity distribution in the NP-HPLC fractions. In most active fractions, fatty acids (FAs), including oleic acid, stearic acid, palmitic acid and myristic acid, were the primary chemicals identified using gas-chromatography mass spectrometry (GC-MS). Chemical measurements of the FAs in house dust extracts revealed a positive and significant correlation with the observed PPARγ1 activity. To test the role of FAs in the activity, a mixture of four FAs was prepared in the ratios measured in the dust samples and tested for activity. The activity of this mixture was 30-50% of the activity observed in the dust extracts, suggesting they were contributing to the observed activity, but also suggesting additional unknown compounds are likely still present in the dust extracts. To tentatively identify sources of FAs in the dust samples, FAs were quantified in human/animal hair, dead skin cells, and cooking oil. FAs were abundant in all samples and our data indicate that all of these may be sources to indoor dust.

  8. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.

    PubMed

    Desch, Michael; Schreiber, Andrea; Schweda, Frank; Madsen, Kirsten; Friis, Ulla G; Weatherford, Eric T; Sigmund, Curt D; Sequeira Lopez, Maria Luisa; Gomez, R Ariel; Todorov, Vladimir T

    2010-03-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse renin gene is regulated by PPARgamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARgamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARgamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPARgamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARgamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARgamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARgamma(fl/fl) mice). We provide evidence that PPARgamma expression was effectively reduced in JG cells of RC-PPARgamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARgamma(fl/fl) than in littermate control RC-PPARgamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPARgamma(fl/fl) mice were almost 2-fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARgamma(wt/wt) and RC-PPARgamma(fl/fl) mice. These data demonstrate that the JG-specific PPARgamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells.

  9. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.

    PubMed

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings. PMID:26710090

  10. Telmisartan increases lipoprotein lipase expression via peroxisome proliferator-activated receptor-alpha in HepG2 cells.

    PubMed

    Yin, Shi Nan; Liu, Min; Jing, Dan Qing; Mu, Yi Ming; Lu, Ju Ming; Pan, Chang Yu

    2014-01-01

    In addition to their hypotensive properties, angiotensin receptor blockers (ARBs) have been shown to exert clinical antidyslipidemic effects. The mechanism underlying these ARB lipid metabolic effects remains unclear. Some ARBs, for example, telmisartan, activate peroxisome proliferator-activated activated receptor-gamma (PPAR-gamma). We hypothesized that PPAR-gamma-activating ARBs might exert antidyslipidemic effects via PPAR-alpha. In this study, we assessed the effect of telmisartan on the expression of PPAR-alpha and lipoprotein lipase (LPL). PPAR-alpha expression was detected by reverse-transcription polymerase chain reaction and Western blot in HepG2 hepatocytes as well as differentiated C2C12 myocytes treated with increasing concentrations of telmisartan (0.1-10 μmol/L) for 48 h. Results showed that 1 μmol/L and 10 μmol/L telmisartan significantly increased the expression of PPAR-alpha mRNA and protein in HepG2 cells (p < 0.01). No effect was shown in differentiated C2C12 cells. Similarly, 1 µmol/L and 10 μmol/L telmisartan significantly increased the expression of LPL mRNA and protein in HepG2 cells (p < 0.01), and this increase was significantly (p < 0.01) inhibited by the PPAR-alpha-specific antagonist MK886. These results indicate that certain of the antidyslipidemic effects of telmisartan might be mediated via increased PPAR-alpha-dependent induction of LPL expression. PMID:24067162

  11. Molecular characterization, transcriptional activity and nutritional regulation of peroxisome proliferator activated receptor gamma in Nile tilapia (Oreochromis niloticus).

    PubMed

    He, An-Yuan; Liu, Cai-Zhi; Chen, Li-Qiao; Ning, Li-Jun; Qin, Jian-Guang; Li, Jia-Ming; Zhang, Mei-Ling; Du, Zhen-Yu

    2015-11-01

    Peroxisome proliferator activated receptor gamma (PPARγ) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARγ in fish are still unclear. This study cloned PPARγ from Nile tilapia (Oreochromis niloticus) referred as NtPPARγ and transfected the NtPPARγ plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARγ was compared in fed and fasted fish. Two transcripts of NtPPARγ varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARγ collaborates with retinoid X-receptor α (NtRXRα) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARγ in human. In the fish fasting trial, the mRNA expression of NtPPARγ1 and NtPPARγ2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARγ was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARγ collaborates with RXRα to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARγ in fish.

  12. Peroxisome proliferator-activated receptor gamma B cell-specific deficient mice have an impaired antibody response1

    PubMed Central

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H.; Murant, Thomas I.; Moshkani, Safiehkhatoon; Sahler, Julie M.; Bottaro, Andrea; Sime, Patricia J.; Phipps, Richard P.

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand activated transcription factor, has important anti-inflammatory and anti-proliferative functions and it has been associated with diseases including diabetes, scarring and atherosclerosis among others. PPARγ is expressed in most bone marrow derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote antibody production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. Here, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development as well as the levels of circulating antigen-specific antibodies during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of antigen-specific antibodies and low numbers of antigen-experienced antibody-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within neither primary nor secondary lymphoid organs during development. This is the first report to show under physiological conditions that PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and antibody production. PMID:23041568

  13. Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

    PubMed

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H; Murant, Thomas I; Moshkani, Safiehkhatoon; Sahler, Julie M; Bottaro, Andrea; Sime, Patricia J; Phipps, Richard P

    2012-11-15

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARγ is expressed in most bone marrow-derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote Ab production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. In this article, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development, as well as the levels of circulating Ag-specific Abs during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of Ag-specific Abs and low numbers of Ag-experienced, Ab-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within primary or secondary lymphoid organs during development. This is the first report, to our knowledge, to show that, under physiological conditions, PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and Ab production.

  14. Polyacetylenes from Notopterygium incisum–New Selective Partial Agonists of Peroxisome Proliferator-Activated Receptor-Gamma

    PubMed Central

    Liu, Xin; Noha, Stefan M.; Malainer, Clemens; Kramer, Matthias P.; Cocic, Amina; Kunert, Olaf; Schinkovitz, Andreas; Heiss, Elke H.; Schuster, Daniela

    2013-01-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a key regulator of glucose and lipid metabolism and therefore an important pharmacological target to combat metabolic diseases. Since the currently used full PPARγ agonists display serious side effects, identification of novel ligands, particularly partial agonists, is highly relevant. Searching for new active compounds, we investigated extracts of the underground parts of Notopterygium incisum, a medicinal plant used in traditional Chinese medicine, and observed significant PPARγ activation using a PPARγ-driven luciferase reporter model. Activity-guided fractionation of the dichloromethane extract led to the isolation of six polyacetylenes, which displayed properties of selective partial PPARγ agonists in the luciferase reporter model. Since PPARγ activation by this class of compounds has so far not been reported, we have chosen the prototypical polyacetylene falcarindiol for further investigation. The effect of falcarindiol (10 µM) in the luciferase reporter model was blocked upon co-treatment with the PPARγ antagonist T0070907 (1 µM). Falcarindiol bound to the purified human PPARγ receptor with a Ki of 3.07 µM. In silico docking studies suggested a binding mode within the ligand binding site, where hydrogen bonds to Cys285 and Glu295 are predicted to be formed in addition to extensive hydrophobic interactions. Furthermore, falcarindiol further induced 3T3-L1 preadipocyte differentiation and enhanced the insulin-induced glucose uptake in differentiated 3T3-L1 adipocytes confirming effectiveness in cell models with endogenous PPARγ expression. In conclusion, we identified falcarindiol-type polyacetylenes as a novel class of natural partial PPARγ agonists, having potential to be further explored as pharmaceutical leads or dietary supplements. PMID:23630612

  15. Peroxisome Proliferator-Activated Receptor γ Level Contributes to Structural Integrity and Component Production of Elastic Fibers in the Aorta.

    PubMed

    Tai, Haw-Chih; Tsai, Pei-Jane; Chen, Ju-Yi; Lai, Chao-Han; Wang, Kuan-Chieh; Teng, Shih-Hua; Lin, Shih-Chieh; Chang, Alice Y W; Jiang, Meei-Jyh; Li, Yi-Heng; Wu, Hua-Lin; Maeda, Nobuyo; Tsai, Yau-Sheng

    2016-06-01

    Loss of integrity and massive disruption of elastic fibers are key features of abdominal aortic aneurysm (AAA). Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to attenuate AAA through inhibition of inflammation and proteolytic degradation. However, its involvement in elastogenesis during AAA remains unclear. PPARγ was highly expressed in human AAA within all vascular cells, including inflammatory cells and fibroblasts. In the aortas of transgenic mice expressing PPARγ at 25% normal levels (Pparg(C) (/-) mice), we observed the fragmentation of elastic fibers and reduced expression of vital elastic fiber components of elastin and fibulin-5. These were not observed in mice with 50% normal PPARγ expression (Pparg(+/-) mice). Infusion of a moderate dose of angiotensin II (500 ng/kg per minute) did not induce AAA but Pparg(+/-) aorta developed flattened elastic lamellae, whereas Pparg(C/-) aorta showed severe destruction of elastic fibers. After infusion of angiotensin II at 1000 ng/kg per minute, 73% of Pparg(C/-) mice developed atypical suprarenal aortic aneurysms: superior mesenteric arteries were dilated with extensive collagen deposition in adventitia and infiltrations of inflammatory cells. Although matrix metalloproteinase inhibition by doxycycline somewhat attenuated the dilation of aneurysm, it did not reduce the incidence nor elastic lamella deterioration in angiotensin II-infused Pparg(C/-) mice. Furthermore, PPARγ antagonism downregulated elastin and fibulin-5 in fibroblasts, but not in vascular smooth muscle cells. Chromatin immunoprecipitation assay demonstrated PPARγ binding in the genomic sequence of fibulin-5 in fibroblasts. Our results underscore the importance of PPARγ in AAA development though orchestrating proper elastogenesis and preserving elastic fiber integrity. PMID:27045031

  16. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-{delta}

    SciTech Connect

    Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming . E-mail: zhuzm@yahoo.com

    2007-03-09

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-{delta} (PPAR-{delta})-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-{delta}. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-{delta}. Furthermore, selective silencing of PPAR-{delta} by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 {+-} 0.06 (n = 3) to 1.91 {+-} 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-{delta} significantly reduced CB1 expression to 0.39 {+-} 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-{delta}. Both CB1 and PPAR-{delta} are intimately involved in therapeutic interventions against a most important cardiovascular risk factor.

  17. [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].

    PubMed

    Jouzeau, Jean-Yves; Moulin, David; Koufany, Meriem; Sebillaud, Sylvie; Bianchi, Arnaud; Netter, Patrick

    2008-01-01

    Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or

  18. Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Mattsson, Anna; Kärrman, Anna; Pinto, Rui; Brunström, Björn

    2015-01-01

    Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα) and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting

  19. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

    SciTech Connect

    Fukuda, Kazuki; Matsumura, Takeshi; Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko; Nakao, Saya; Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji; Kawada, Teruo; Nishikawa, Takeshi; Araki, Eiichi

    2015-01-30

    Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects

  20. Molecular characterization, transcriptional activity and nutritional regulation of peroxisome proliferator activated receptor gamma in Nile tilapia (Oreochromis niloticus).

    PubMed

    He, An-Yuan; Liu, Cai-Zhi; Chen, Li-Qiao; Ning, Li-Jun; Qin, Jian-Guang; Li, Jia-Ming; Zhang, Mei-Ling; Du, Zhen-Yu

    2015-11-01

    Peroxisome proliferator activated receptor gamma (PPARγ) is a master regulator in lipid metabolism and widely exists in vertebrates. However, the molecular structure and transcriptional activity of PPARγ in fish are still unclear. This study cloned PPARγ from Nile tilapia (Oreochromis niloticus) referred as NtPPARγ and transfected the NtPPARγ plasmids into HEK-293 cells to explore its mechanism of transcriptional regulation in fish. The expression of NtPPARγ was compared in fed and fasted fish. Two transcripts of NtPPARγ varied at the 5'-untranslated region and the DNA binding domain was highly conserved. Thirty-nine amino acid residues in the ligand binding domain in Nile tilapia were different from those in human. Two transcripts showed different expression profiles in 11 tissues, but both were highly expressed in liver, intestine and kidney. The transcriptional activity assay showed that NtPPARγ collaborates with retinoid X-receptor α (NtRXRα) to regulate the expression of Nile tilapia fatty acid binding protein 4 (FABP4), the compartment of which have been identified as the target gene of PPARγ in human. In the fish fasting trial, the mRNA expression of NtPPARγ1 and NtPPARγ2 in intestine and liver at 3h post-feeding (HPF) was lower than those at 8 HPF, 24 HPF and in fish fasted for 36h, but was relatively stable in kidney among different feeding treatments. In conclusion, the DNA binding domain in PPARγ was highly conserved, while the ligand binding domain was moderately conserved. In Nile tilapia, the PPARγ collaborates with RXRα to perform transcriptional regulation of FABP4 at least in vitro. The plasmid system established in this study along with a cell line from Nile tilapia will be useful tools for the further functional study of PPARγ in fish. PMID:26002036

  1. Ligand specific variation in cardiac response to stimulation of peroxisome proliferator-activated receptor-alpha in spontaneously hypertensive rat.

    PubMed

    Ismael, Saifudeen; Purushothaman, Sreeja; Harikrishnan, V S; Nair, R Renuka

    2015-08-01

    Left ventricular hypertrophy (LVH) is an independent risk factor for cardiac failure. Reduction of LVH has beneficial effects on the heart. LVH is associated with shift in energy substrate preference from fatty acid to glucose, mediated by down regulation of peroxisome proliferator-activated receptor-alpha (PPAR-α). As long-term dependence on glucose can promote adverse cardiac remodeling, it was hypothesized that, prevention of metabolic shift by averting down regulation of PPAR-α can reduce cardiac remodeling in spontaneously hypertensive rat (SHR). Cardiac response to stimulation of PPAR-α presumably depends on the type of ligand used. Therefore, the study was carried out in SHR, using two different PPAR-α ligands. SHR were treated with either fenofibrate (100 mg/kg/day) or medium-chain triglyceride (MCT) Tricaprylin (5% of diet) for 4 months. Expression of PPAR-α and medium-chain acylCoA dehydrogenase served as markers, for stimulation of PPAR-α. Both ligands stimulated PPAR-α. Decrease of blood pressure was observed only with fenofibrate. LVH was assessed from heart-weight/body weight ratio, histology and brain natriuretic peptide expression. As oxidative stress is linked with hypertrophy, serum and cardiac malondialdehyde and cardiac 3-nitrotyrosine levels were determined. Compared to untreated SHR, LVH and oxidative stress were lower on supplementation with MCT, but higher on treatment with fenofibrate. The observations indicate that reduction of blood pressure is not essentially accompanied by reduction of LVH, and that, progressive cardiac remodeling can be prevented with decrease in oxidative stress. Contrary to the notion that reactivation of PPAR-α is detrimental; the study substantiates that cardiac response to stimulation of PPAR-α is ligand specific. PMID:25976666

  2. Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome

    PubMed Central

    Hatami, Mehdi; Saidijam, Massoud; Yadegarzari, Reza; Borzuei, Shiva; Soltanian, Alireza; Arian, Marzieh Safi

    2016-01-01

    Regulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene plays an important role in controlling the metabolism of lipids and inflammatory processes. Therefore, it can be associated with the pathogenesis of metabolic syndrome (MetS). The purpose of this study was to determine the expression of this gene in peripheral blood mononuclear cells (PBMC) in patients with metabolic syndrome. Using real-time polymerase chain reaction (PCR), mRNA expression of PPAR-γ was found in PBMC from 37 subjects with MetS and 30 healthy controls. Serum levels of glucose and lipid profiles were measured. The total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) test. Malondialdehyde (MDA) was determined using a fluorimetric method. Total oxidant status (TOS) in serum was assayed according to oxidation of ferric to ferrous in the presence of methyl orange. Super oxide dismutase (SOD) activity was measured using a Randox kit. Expression of PPAR-γ gene was significantly increased in patients with MetS compared to the control subjects (p=0.002). There was no difference in serum levels of TAC, MDA and SOD between the two study groups, but a significant difference was observed in the TOS (p=0.03). Serum levels of triglycerides and glucose were significantly higher in subjects with MetS. According to the results of our study, an increase in the expression of PPAR-γ in subjects with MetS indicated a possible role of PPAR-γ in the pathogenesis of this disease. PMID:27689030

  3. CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver

    PubMed Central

    Makia, Ngome L.

    2016-01-01

    Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARα response element located at position −2109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARα to this PPARα response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators. PMID:26467040

  4. CYP2C8 Is a Novel Target of Peroxisome Proliferator-Activated Receptor α in Human Liver.

    PubMed

    Makia, Ngome L; Goldstein, Joyce A

    2016-01-01

    Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically active epoxyeicosatrienoic acids. Previous studies from our laboratory showed that microRNA 107 (miR107) and microRNA 103 downregulate CYP2C8 post-transcriptionally. miR107 is located in intron 5 of the pantothenate kinase 1 (PANK1) gene. p53 has been reported to coregulate the induction of PANK1 and miR107. Here, we examine the possible downregulation of CYP2C8 by drugs capable of inducing miR107. Hypolipidemic drugs, such as bezafibrate, known activators of the peroxisome proliferator-activated receptor α (PPARα), induce both the PANK1 gene and miR107 (∼2.5-fold) in primary human hepatocytes. Surprisingly, CYP2C8 mRNA and protein levels were induced by bezafibrate. CYP2C8 promoter activity was increased by ectopic expression of PPARα in HepG2 cells, with a further increase after bezafibrate (∼18-fold), 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio acetic acid (∼10-fold) treatment, or the antidiabetic drug rosiglitazone, all known PPAR activators. Promoter sequence analyses, deletion studies, mutagenesis studies, and electrophoretic mobility shift assays identified a PPARα response element located at position -2109 base pair relative to the translation start site of CYP2C8. Chromatin immunopreciptation assay analysis confirmed recruitment of PPARα to this PPARα response element after bezafibrate treatment of human hepatocytes. Thus, we show for the first time that CYP2C8 is transcriptionally regulated by PPARα, suggesting the potential for drug-drug interactions due to upregulation of CYP2C8 by PPAR activators. PMID:26467040

  5. Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8

    PubMed Central

    Thomas, Maria; Winter, Stefan; Klumpp, Britta; Turpeinen, Miia; Klein, Kathrin; Schwab, Matthias; Zanger, Ulrich M.

    2015-01-01

    The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ∼60 and ∼50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions –2762/–2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype. PMID:26582990

  6. Peroxisome proliferator-activated receptor gamma in the human pituitary gland: expression and splicing pattern in adenomas versus normal pituitary.

    PubMed

    Occhi, G; Albiger, N; Berlucchi, S; Gardiman, M; Scanarini, M; Scienza, R; Fassina, A; Mantero, F; Scaroni, C

    2007-07-01

    Pituitary adenomas are slow-growing tumours arising within the pituitary gland. If secreting, they give rise to well-known syndromes such as Cushing's disease or acromegaly; when hormonally inactive, they come to clinical attention often with local mass effects or pituitary deficiency. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor with a key role in fat and glucose metabolism, but also involved in several neoplasia, has recently been detected in pituitary adenomas. In the present study, we evaluated the occurrence and splicing profile of PPARgamma in 43 cases of pituitary adenoma of different subtypes and compared it to 12 normal pituitary glands. By real-time polymerase chain reaction, PPARgamma was expressed as much in adrenocorticotrophic hormone (ACTH)-secreting and ACTH-silent adenomas as in controls, with a moderate underexpression in somatotrophinomas and prolactinomas and overexpression in 54% of nonfunctioning pituitary adenomas (NFPA). There was no apparent qualitative change in the splicing profile of pathological pituitary glands, nor was the presence of specific isoforms with dominant negative effects against PPARgamma detected. Western blotting revealed similar expression levels in the different subgroups of pituitary adenomas and normal glands. Immunohistochemistry confirmed PPARgamma expression in approximately one-half of analysed samples. The intra- and intergroup differences observed in pituitary adenomas may represent new elements in the process of understanding the different clinical responses of Cushing's and Nelson patients to PPARgamma-ligand treatment. Moreover, the higher level of PPARgamma expression detected in the NFPA subgroup may suggest its possible role as a molecular target in these pituitary adenomas, paving the way for investigations on the effectiveness of treatment with thiazolidinediones in such patients. PMID:17561883

  7. Differentiation of Trophoblast Giant Cells and Their Metabolic Functions Are Dependent on Peroxisome Proliferator-Activated Receptor β/δ

    PubMed Central

    Nadra, Karim; Anghel, Silvia I.; Joye, Elisabeth; Tan, Nguan Soon; Basu-Modak, Sharmila; Trono, Didier; Wahli, Walter; Desvergne, Béatrice

    2006-01-01

    Mutation of the nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) severely affects placenta development, leading to embryonic death at embryonic day 9.5 (E9.5) to E10.5 of most, but not all, PPARβ/δ-null mutant embryos. While very little is known at present about the pathway governed by PPARβ/δ in the developing placenta, this paper demonstrates that the main alteration of the placenta of PPARβ/δ-null embryos is found in the giant cell layer. PPARβ/δ activity is in fact essential for the differentiation of the Rcho-1 cells in giant cells, as shown by the severe inhibition of differentiation once PPARβ/δ is silenced. Conversely, exposure of Rcho-1 cells to a PPARβ/δ agonist triggers a massive differentiation via increased expression of 3-phosphoinositide-dependent kinase 1 and integrin-linked kinase and subsequent phosphorylation of Akt. The links between PPARβ/δ activity in giant cells and its role on Akt activity are further strengthened by the remarkable pattern of phospho-Akt expression in vivo at E9.5, specifically in the nucleus of the giant cells. In addition to this phosphatidylinositol 3-kinase/Akt main pathway, PPARβ/δ also induced giant cell differentiation via increased expression of I-mfa, an inhibitor of Mash-2 activity. Finally, giant cell differentiation at E9.5 is accompanied by a PPARβ/δ-dependent accumulation of lipid droplets and an increased expression of the adipose differentiation-related protein (also called adipophilin), which may participate to lipid metabolism and/or steroidogenesis. Altogether, this important role of PPARβ/δ in placenta development and giant cell differentiation should be considered when contemplating the potency of PPARβ/δ agonist as therapeutic agents of broad application. PMID:16581799

  8. Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA) and Agonists to Peroxisome Proliferator-Activated Receptors.

    PubMed

    Mattsson, Anna; Kärrman, Anna; Pinto, Rui; Brunström, Björn

    2015-01-01

    Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA), and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα) and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic profile resulting

  9. Interaction between peroxisome proliferator- activated receptor gamma polymorphism and overweight on diabetic retinopathy in a Chinese case-control study

    PubMed Central

    Wang, Yan; Wang, Xin-Hua; Li, Ruo-Xi

    2015-01-01

    Background: Peroxisome proliferator-activated receptors γ (PPAR γ) and overweight were both associated with diabetic retinopathy (DR), so the aim of this study was to investigate the association of four single nucleotide polymorphisms (SNPs) of PPAR γ with DR and additional role of gene-BMI interaction. Methods: A total of 500 patients with T2DM (236 men, 264 women), with a mean age of 54.3 ± 15.8 years old, were selected, including 247 diabetic retinopathy patients and 253 controls. Four SNPs were selected for genotyping in the case-control study: rs1805192, rs709158, rs3856806, rs4684847. Logistic regression model was used to examine the interaction between SNP and overweight on DR, odds ratio (OR) and 95% confident interval (95% CI) were calculated. Results: The carriers of C allele of the rs1805192 polymorphism revealed decreased DR risk than those with Pro/Pro variants (Pro/Ala+Ala/Ala versus Pro/Pro, adjusted OR (95% CI)=0.86 (0.65-0.96), P=0.012), after adjusting for covariates. We also found that obese subjects with Pro/Ala or Ala/Ala variants genotype have lowest DR risk, compared to obese subjects with Pro/Pro genotype or non- obese subjects with Pro/Ala or Ala/Ala (OR=0.40, 95% CI=0.32-0.63), after covariates adjustment. Conclusions: Our results support an important association between rs1805192 minor allele (Ala allele) of PPAR γ and DR, the interaction analysis shown a combined effect of Ala- BMI interaction on DR. PMID:26885119

  10. Transcription coactivator peroxisome proliferator-activated receptor-binding protein/mediator 1 deficiency abrogates acetaminophen hepatotoxicity

    PubMed Central

    Jia, Yuzhi; Guo, Grace L.; Surapureddi, Sailesh; Sarkar, Joy; Qi, Chao; Guo, Dongsheng; Xia, Jun; Kashireddi, Papreddy; Yu, Songtao; Cho, Young-Wook; Rao, M. Sambasiva; Kemper, Byron; Ge, Kai; Gonzalez, Frank J.; Reddy, Janardan K.

    2005-01-01

    Peroxisome proliferator-activated receptor-binding protein (PBP), also known as thyroid hormone receptor-associated protein 220/vitamin D receptor-interacting protein 205/mediator 1, an anchor for multisubunit mediator transcription complex, functions as a transcription coactivator for nuclear receptors. Disruption of the PBP gene results in embryonic lethality around embryonic day 11.5 by affecting placental and multiorgan development. Here, we report that targeted deletion of PBP in liver parenchymal cells (PBPLiv-/-) results in the abrogation of hypertrophic and hyperplastic influences in liver mediated by constitutive androstane receptor (CAR) ligands phenobarbital (PB) and 1,4-bis-[2-(3,5-dichloropyridyloxy)]benzene, and of acetaminophen-induced hepatotoxicity. CAR interacts with the two nuclear receptor-interacting LXXLL (L, leucine; X, any amino acid) motifs in PBP in a ligand-dependent manner. We also show that PBP interacts with the C-terminal portion of CAR, suggesting that PBP is involved in the regulation of CAR function. Although the full-length PBP only minimally increased CAR transcriptional activity, a truncated form of PBP (amino acids 487-735) functioned as a dominant negative repressor, establishing that PBP functions as a coactivator for CAR. A reduction in CAR mRNA and protein level observed in PBPLiv-/- mouse liver suggests that PBP may regulate hepatic CAR expression. PBP-deficient hepatocytes in liver failed to reveal PB-dependent translocation of CAR to the nucleus. Adenoviral reconstitution of PBP in PBPLiv-/- mouse livers restored PB-mediated nuclear translocation of CAR as well as inducibility of CYP1A2, CYP2B10, CYP3A11, and CYP7A1 expression. We conclude that transcription coactivator PBP/TRAP220/MED1 is involved in the regulation of hepatic CAR function and that PBP deficiency in liver abrogates acetaminophen hepatotoxicity. PMID:16109766

  11. Peroxisome Proliferator Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3 Mediated Epithelial Mesenchymal Transition

    PubMed Central

    Reka, Ajaya Kumar; Kurapati, Himabindu; Narala, Venkata R; Bommer, Guido; Chen, Jun; Standiford, Theodore J.; Keshamouni, Venkateshwar G.

    2011-01-01

    Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, and resistance to apoptosis, evading immune surveillance and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here we demonstrate that activation of peroxisome proliferator activated receptor (PPAR) -γ inhibits TGF-β-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (Troglitazone and Rosiglitazone) or by a constitutively-active form of PPAR-γ prevents TGF-β-induced loss of E-cadherin expression and inhibited the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and MMPs. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA mediated knockdown of PPAR-γ, indicating that the ligand induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA demonstrated that TGF-β-induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β-induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently PPAR-γ activation prevented TGF-ß-induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells both significantly inhibited TGF-β-induced experimental metastasis in Scid-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data demonstrates that these ligands may serve as potential therapeutic agents to inhibit metastasis. PMID:21159608

  12. Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome.

    PubMed

    Hatami, Mehdi; Saidijam, Massoud; Yadegarzari, Reza; Borzuei, Shiva; Soltanian, Alireza; Arian, Marzieh Safi; Goodarzi, Mohammad Taghi

    2016-09-01

    Regulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene plays an important role in controlling the metabolism of lipids and inflammatory processes. Therefore, it can be associated with the pathogenesis of metabolic syndrome (MetS). The purpose of this study was to determine the expression of this gene in peripheral blood mononuclear cells (PBMC) in patients with metabolic syndrome. Using real-time polymerase chain reaction (PCR), mRNA expression of PPAR-γ was found in PBMC from 37 subjects with MetS and 30 healthy controls. Serum levels of glucose and lipid profiles were measured. The total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) test. Malondialdehyde (MDA) was determined using a fluorimetric method. Total oxidant status (TOS) in serum was assayed according to oxidation of ferric to ferrous in the presence of methyl orange. Super oxide dismutase (SOD) activity was measured using a Randox kit. Expression of PPAR-γ gene was significantly increased in patients with MetS compared to the control subjects (p=0.002). There was no difference in serum levels of TAC, MDA and SOD between the two study groups, but a significant difference was observed in the TOS (p=0.03). Serum levels of triglycerides and glucose were significantly higher in subjects with MetS. According to the results of our study, an increase in the expression of PPAR-γ in subjects with MetS indicated a possible role of PPAR-γ in the pathogenesis of this disease. PMID:27689030

  13. Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats.

    PubMed

    Buckingham, R E; Al-Barazanji, K A; Toseland, C D; Slaughter, M; Connor, S C; West, A; Bond, B; Turner, N C; Clapham, J C

    1998-08-01

    Rosiglitazone (BRL 49653), a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist and potent insulin action-enhancing agent, was given in the diet (50 micromol/kg of diet) to male Zucker rats ages 6-7 weeks for 9 months (prevention group). In this treatment mode, rosiglitazone prolonged the time to onset of proteinuria from 3 to 6 months and markedly reduced the rate of its subsequent progression. Progression was also retarded when treatment was commenced (intervention group) after proteinuria had become established (4 months; ages 24-25 weeks). In either treatment mode, rosiglitazone normalized urinary N-acetyl-beta-D-glucosaminidase activity, a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure that occurred coincidentally with the development of proteinuria in Zucker fatty control rats. The renal protective action of rosiglitazone was verified morphologically. Thus in the prevention group there was an absence of the various indexes of chronic nephropathy that were prominent in the Zucker fatty control group, namely, glomerulosclerosis, dilated tubules containing proteinaceous casts, a loss of functional microvilli on the tubular epithelium, and varying degrees of chronic interstitial nephritis. An intermediate pathology was observed in the intervention group. Also, pancreatic islet hyperplasia, ultrastructural evidence of beta-cell work hypertrophy, and derangement of alpha-cell distribution within the islet were prominent features of Zucker fatty control rats, but these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment. These data demonstrate that treatment of Zucker fatty rats with rosiglitazone produced substantial protection over a prolonged period against the development and progression of renal injury and the adaptive changes to pancreatic islet morphology caused by sustained hyperinsulinemia. PMID:9703335

  14. Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

    SciTech Connect

    O'Sullivan, Saoirse E. . E-mail: Saoirse.o'sullivan@nottingham.ac.uk; Tarling, Elizabeth J.; Bennett, Andrew J.; Kendall, David A.; Randall, Michael D.

    2005-11-25

    Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.

  15. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

    PubMed

    Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John

    2009-09-01

    Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.

  16. Peroxisome Proliferator-Activated Receptor-γGene Expression and Its Association with Oxidative Stress in Patients with Metabolic Syndrome

    PubMed Central

    Hatami, Mehdi; Saidijam, Massoud; Yadegarzari, Reza; Borzuei, Shiva; Soltanian, Alireza; Arian, Marzieh Safi

    2016-01-01

    Regulation of the peroxisome proliferator-activated receptor-γ (PPAR-γ) gene plays an important role in controlling the metabolism of lipids and inflammatory processes. Therefore, it can be associated with the pathogenesis of metabolic syndrome (MetS). The purpose of this study was to determine the expression of this gene in peripheral blood mononuclear cells (PBMC) in patients with metabolic syndrome. Using real-time polymerase chain reaction (PCR), mRNA expression of PPAR-γ was found in PBMC from 37 subjects with MetS and 30 healthy controls. Serum levels of glucose and lipid profiles were measured. The total antioxidant capacity (TAC) was measured using the ferric reducing ability of plasma (FRAP) test. Malondialdehyde (MDA) was determined using a fluorimetric method. Total oxidant status (TOS) in serum was assayed according to oxidation of ferric to ferrous in the presence of methyl orange. Super oxide dismutase (SOD) activity was measured using a Randox kit. Expression of PPAR-γ gene was significantly increased in patients with MetS compared to the control subjects (p=0.002). There was no difference in serum levels of TAC, MDA and SOD between the two study groups, but a significant difference was observed in the TOS (p=0.03). Serum levels of triglycerides and glucose were significantly higher in subjects with MetS. According to the results of our study, an increase in the expression of PPAR-γ in subjects with MetS indicated a possible role of PPAR-γ in the pathogenesis of this disease.

  17. Differential effects of peroxisome proliferator-activated receptor agonists on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells.

    PubMed

    Yousefi, B; Samadi, N; Baradaran, B; Rameshknia, V; Shafiei-Irannejad, V; Majidinia, M; Targhaze, N; Zarghami, N

    2015-01-01

    P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) in tumor cells is still a main obstacle for the chemotherapeutic treatment of cancers. Therefore, identification of safe and effective MDR reversing compounds with minimal adverse side effects is an important approach in the cancer treatment. Studies show that peroxisome proliferator-activated receptor (PPARs) ligands can inhibit cell growth in many cancers. Here, we investigated the effect of different PPAR agonists include fenofibrate, troglitazone and aleglitazar on doxorubicin-resistant human myelogenous leukemia (K562/DOX) cells. The effects of doxorubicin (DOX) following treatment with PPAR agonists on cell viability were evaluated using MTT assay and the reversal fold (RF) values. Rhodamine123 (Rh123) assays were used to determine P-gp functioning. P-gp mRNA/protein expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and western blot analysis after incubation with troglitazone and aleglitazar. Our results showed that troglitazone and aleglitazar significantly enhanced the cytotoxicity of DOX and decreased the RF values in K562/DOX cells, however, no such results were found for fenofibrate. Troglitazone and aleglitazar significantly down regulated P-gp expression in K562/DOX cells; in addition, the present study revealed that aleglitazar elevated intracellular accumulation of Rh123in K562/DOX cells as short-term effects, which also contribute to the reversal of MDR. These findings show that troglitazone and especially aleglitazar exhibited potent effects in the reversal of P-gp-mediated MDR, suggesting that these compounds may be effective for combination therapy strategies and circumventing MDR in K562/DOX cells to other conventional chemotherapeutic drugs. PMID:26718439

  18. Urine acidification has no effect on peroxisome proliferator-activated receptor (PPAR) signaling or epidermal growth factor (EGF) expression in rat urinary bladder urothelium

    SciTech Connect

    Achanzar, William E. Moyer, Carolyn F.; Marthaler, Laura T.; Gullo, Russell; Chen, Shen-Jue; French, Michele H.; Watson, Linda M.; Rhodes, James W.; Kozlosky, John C.; White, Melvin R.; Foster, William R.; Burgun, James J.; Car, Bruce D.; Cosma, Gregory N.; Dominick, Mark A.

    2007-09-15

    We previously reported prevention of urolithiasis and associated rat urinary bladder tumors by urine acidification (via diet acidification) in male rats treated with the dual peroxisome proliferator-activated receptor (PPAR){alpha}/{gamma} agonist muraglitazar. Because urine acidification could potentially alter PPAR signaling and/or cellular proliferation in urothelium, we evaluated urothelial cell PPAR{alpha}, PPAR{delta}, PPAR{gamma}, and epidermal growth factor receptor (EGFR) expression, PPAR signaling, and urothelial cell proliferation in rats fed either a normal or an acidified diet for 5, 18, or 33 days. A subset of rats in the 18-day study also received 63 mg/kg of the PPAR{gamma} agonist pioglitazone daily for the final 3 days to directly assess the effects of diet acidification on responsiveness to PPAR{gamma} agonism. Urothelial cell PPAR{alpha} and {gamma} expression and signaling were evaluated in the 18- and 33-day studies by immunohistochemical assessment of PPAR protein (33-day study only) and quantitative real-time polymerase chain reaction (qRT-PCR) measurement of PPAR-regulated gene expression. In the 5-day study, EGFR expression and phosphorylation status were evaluated by immunohistochemical staining and egfr and akt2 mRNA levels were assessed by qRT-PCR. Diet acidification did not alter PPAR{alpha}, {delta}, or {gamma} mRNA or protein expression, PPAR{alpha}- or {gamma}-regulated gene expression, total or phosphorylated EGFR protein, egfr or akt2 gene expression, or proliferation in urothelium. Moreover, diet acidification had no effect on pioglitazone-induced changes in urothelial PPAR{gamma}-regulated gene expression. These results support the contention that urine acidification does not prevent PPAR{gamma} agonist-induced bladder tumors by altering PPAR{alpha}, {gamma}, or EGFR expression or PPAR signaling in rat bladder urothelium.

  19. Protection of neurons and microglia against ethanol in a mouse model of fetal alcohol spectrum disorders by peroxisome proliferator-activated receptor-γ agonists.

    PubMed

    Kane, Cynthia J M; Phelan, Kevin D; Han, Lihong; Smith, Renea R; Xie, Jin; Douglas, James C; Drew, Paul D

    2011-06-01

    Fetal alcohol spectrum disorders (FASD) result from ethanol exposure to the developing fetus and are the most common cause of mental retardation in the United States. These disorders are characterized by a variety of neurodevelopmental and neurodegenerative anomalies which result in significant lifetime disabilities. Thus, novel therapies are required to limit the devastating consequences of FASD. Neuropathology associated with FASD can occur throughout the central nervous system (CNS), but is particularly well characterized in the developing cerebellum. Rodent models of FASD have previously demonstrated that both Purkinje cells and granule cells, which are the two major types of neurons in the cerebellum, are highly susceptible to the toxic effects of ethanol. The current studies demonstrate that ethanol decreases the viability of cultured cerebellar granule cells and microglial cells. Interestingly, microglia have dual functionality in the CNS. They provide trophic and protective support to neurons. However, they may also become pathologically activated and produce inflammatory molecules toxic to parenchymal cells including neurons. The findings in this study demonstrate that the peroxisome proliferator-activated receptor-γ agonists 15-deoxy-Δ12,15 prostaglandin J2 and pioglitazone protect cultured granule cells and microglia from the toxic effects of ethanol. Furthermore, investigations using a newly developed mouse model of FASD and stereological cell counting methods in the cerebellum elucidate that ethanol administration to neonates is toxic to both Purkinje cell neurons as well as microglia, and that in vivo administration of PPAR-γ agonists protects these cells. In composite, these studies suggest that PPAR-γ agonists may be effective in limiting ethanol-induced toxicity to the developing CNS.

  20. A Comparison of the Roles of Peroxisome Proliferator-Activated Receptor and Retinoic Acid Receptor on CYP26 Regulation

    PubMed Central

    Tay, Suzanne; Dickmann, Leslie; Dixit, Vaishali

    2010-01-01

    The cytochrome P450 26 family is believed to be responsible for all-trans-retinoic acid (atRA) metabolism and elimination in the human fetus and adults. CYP26A1 and CYP26B1 mRNA is expressed in a tissue-specific manner, and mice in which the CPY26 isoform has been knocked out show distinct malformations and lethality. The aim of this study was to determine differences in CYP26A1 and CYP26B1 regulation and expression. Analysis of CYP26A1 and CYP26B1 expression in a panel of 57 human livers showed CYP26A1 to be the major CYP26 isoform present in the liver, and its expression to be subject to large interindividual variability between donors. CYP26A1 and retinoic acid receptor (RAR) β were found to be greatly inducible by atRA in HepG2 cells, whereas CYP26B1, RARα, and RARγ were induced to a much lesser extent. Based on treatments with RAR isoform-selective ligands, RARα is the major isoform responsible for CYP26A1 and RARβ induction in HepG2 cells. Classic cytochrome P450 inducers did not affect CYP26 transcription, whereas the peroxisome proliferator-activated receptor (PPAR) γ agonists pioglitazone and rosiglitazone up-regulated CYP26B1 transcription by as much as 209- ± 80-fold and CYP26A1 by 10-fold. RARβ was also up-regulated by pioglitazone and rosiglitazone. CYP26B1 induction by PPARγ agonists was abolished by the irreversible PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662), whereas RARβ and CYP26A1 induction was unaffected by GW9662. Overall, the results of this study suggest that CYP26B1 and CYP26A1 are regulated by different nuclear receptors, resulting in tissue-specific expression patterns. The fact that drugs can alter the expression of CYP26 enzymes may have toxicological and therapeutic importance. PMID:19884280

  1. Association between peroxisome proliferator-activated receptor-alpha, delta, and gamma polymorphisms and risk of coronary heart disease

    PubMed Central

    Qian, Yufeng; Li, Peiwei; Zhang, Jinjie; Shi, Yu; Chen, Kun; Yang, Jun; Wu, Yihua; Ye, Xianhua

    2016-01-01

    Abstract Objectives: Risk of coronary heart disease (CHD) has been suggested to be associated with polymorphisms of peroxisome proliferator-activated receptors (PPARs), while the results were controversial. We aimed to systematically assess the association between PPAR polymorphisms and CHD risk. Methods: A case–control study with 446 subjects was conducted to evaluate the association between CHD risk and C161T polymorphism, which was of our special interest as this polymorphism showed different effects on risks of CHD and acute coronary syndrome (ACS). Meta-analyses were conducted to assess all PPAR polymorphisms. Either a fixed- or a random-effects model was adopted to estimate overall odds ratios (ORs). Results: In the case–control study, T allele carriers of C161T polymorphism were not significantly associated with CHD risk (Odds ratio (OR) = 0.74, 95% confidence interval (CI) 0.47–1.15, P = 0.19), while T allele carriers showed higher risk of ACS (OR = 1.63, 95% CI 1.00–2.65, P = 0.048). The meta-analysis indicated that compared with CC homozygous, T allele carriers had lower CHD risk (OR = 0.69, 95% CI 0.59–0.82, P < 0.001) but higher ACS risk (OR = 1.43, 95% CI 1.09–1.87, P = 0.010). Three other polymorphisms were also found to be significantly associated with CHD risk under dominant model: PPAR-alpha intron 7G/C polymorphism (CC+GC vs GG, OR 1.42, 95% CI 1.13–1.78, P = 0.003), L162V polymorphism (VV+LV vs LL, OR 0.74, 95% CI 0.56–0.97, P = 0.031), and PPAR-delta +294T/C polymorphism (CC+TC vs TT, OR 1.51, 95% CI 1.12–2.05, P = 0.007). Conclusions: The results suggested that PPAR-alpha intron 7G/C and L162V, PPAR-delta +294T/C and PPAR-gamma C161T polymorphisms could affect CHD susceptibility, and C161T polymorphism might have different effects on CHD and ACS. PMID:27512842

  2. The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene

    PubMed Central

    Yoo, Hong Sik; Cichocki, Joseph A.; Kim, Sungkyoon; Venkatratnam, Abhishek; Iwata, Yasuhiro; Kosyk, Oksana; Bodnar, Wanda; Sweet, Stephen; Knap, Anthony; Wade, Terry; Campbell, Jerry; Clewell, Harvey J.; Melnyk, Stepan B.; Chiu, Weihsueh A.; Rusyn, Ivan

    2015-01-01

    Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor

  3. Glycogen content regulates peroxisome proliferator activated receptor-∂ (PPAR-∂) activity in rat skeletal muscle.

    PubMed

    Philp, Andrew; MacKenzie, Matthew G; Belew, Micah Y; Towler, Mhairi C; Corstorphine, Alan; Papalamprou, Angela; Hardie, D Grahame; Baar, Keith

    2013-01-01

    Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, p<0.05), nuclear AMPK-α2 and PGC-1α, but no difference in AMPK-α1 activity compared to CON. In addition, PPAR-∂ binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-∂ activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-∂ and glycogen content/substrate availability. The present study is the first to examine PPAR-∂ activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal muscle in

  4. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors.

    PubMed

    Qian, Guofeng; Fan, Wei; Ahlemeyer, Barbara; Karnati, Srikanth; Baumgart-Vogt, Eveline

    2015-01-01

    Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression

  5. The mouse CCR2 gene is regulated by two promoters that are responsive to plasma cholesterol and peroxisome proliferator-activated receptor {gamma} ligands

    SciTech Connect

    Chen Yiming; Green, Simone R.; Ho, Jessica; Li, Andrew; Almazan, Felizidad; Quehenberger, Oswald . E-mail: oquehenberger@ucsd.edu

    2005-06-24

    We have previously shown that the expression of monocyte CCR2, the receptor for monocyte chemoattractant protein-1, is induced by plasma cholesterol. The present study examines the mechanisms that regulate monocyte CCR2 expression in hypercholesterolemia using a mouse model. Our data demonstrate that in the mouse, CCR2 expression in circulating monocytes is controlled by two promoters P1 and P2. The two distinct transcripts, which encode the same protein, are produced by alternative splicing in the 5'-untranslated region. Both promoters are constitutively active, but only P2 is stimulated by cholesterol. However, both promoters are repressed by peroxisome proliferator-activated receptor {gamma}.

  6. Identification of glabridin as a bioactive compound in licorice (Glycyrrhiza glabra L.) extract that activates human peroxisome proliferator-activated receptor gamma (PPARγ).

    PubMed

    Rebhun, John F; Glynn, Kelly M; Missler, Stephen R

    2015-10-01

    Licorice, the root and stolons of the Glycyrrhiza plant (Fabaceae), has been used for centuries as a food additive (sweetener), in cosmetics, and in traditional medicine. In this research, we provide evidence that licorice extract activates peroxisome proliferator-activated receptor gamma (PPARγ) and, as identified through HPLC fractionation and mass spectroscopy, one of the activating phytochemicals is glabridin. Glabridin was shown to bind to and activate PPARγ. It was also shown to activate PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands and that the expression was blocked by a PPARγ specific antagonist.

  7. Identification of evodiamine as the bioactive compound in evodia (Evodia rutaecarpa Benth.) fruit extract that activates human peroxisome proliferator-activated receptor gamma (PPARγ).

    PubMed

    Rebhun, John F; Roloff, Samantha J; Velliquette, Rodney A; Missler, Stephen R

    2015-03-01

    The dried unripe fruit from Evodia rutaecarpa Benth., known as Wu zhu yu in China, has long been used in traditional Chinese medicine. In this research, we provide evidence that evodia fruit extract activates peroxisome proliferator-activated receptor gamma (PPARγ) and, as identified through HPLC fractionation and mass spectroscopy, the activating phytochemical is evodiamine. Evodiamine was shown to bind to and activate PPARγ. It was also shown to activate PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands and that the expression was blocked by a PPARγ specific antagonist.

  8. Immunotoxicity of perfluorooctanoic acid and perfluorooctane sulfonate and the role of peroxisome proliferator-activated receptor alpha

    EPA Science Inventory

    Peroxisome proliferators, including perfluorooctanoic acid (PFOA), are environmentally widespread and persistent and multiple toxicities have been reported in experimental animals and humans. These compounds trigger biological activity via activation of the alpha isotype of pero...

  9. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors

    PubMed Central

    Qian, Guofeng; Karnati, Srikanth; Baumgart-Vogt, Eveline

    2015-01-01

    Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression

  10. Nuclear Factor Kappa B Activation and Peroxisome Proliferator-activated Receptor Transactivational Effects of Chemical Components of the Roots of Polygonum multiflorum

    PubMed Central

    Sun, Ya Nan; Li, Wei; Song, Seok Bean; Yan, Xi Tao; Yang, Seo Young; Kim, Young Ho

    2016-01-01

    Background: Polygonum multiflorum is well-known as “Heshouwu” in traditional Chinese herbal medicine. In Northeast Asia, it is often used as a tonic to prevent premature aging of the kidney and liver, tendons, and bones and strengthening of the lower back and knees. Objective: To research the anti-inflammatory activities of components from P. multiflorum. Materials and Methods: The compounds were isolated by a combination of silica gel and YMC R-18 column chromatography, and their structures were identified by analysis of spectroscopic data (1D, 2D-nuclear magnetic resonance, and mass spectrometry). The anti-inflammatory activities of the isolated compounds 1−15 were evaluated by luciferase reporter gene assays. Results: Fifteen compounds (1–15) were isolated from the roots of P. multiflorum. Compounds 1−5 and 14−15 significantly inhibited tumor necrosis factor-α-induced nuclear factor kappa B-luciferase activity, with IC50 values of 24.16-37.56 μM. Compounds 1−5 also greatly enhanced peroxisome proliferator-activated receptors transcriptional activity with EC50 values of 18.26−31.45 μM. Conclusion: The anthraquinone derivatives were the active components from the roots of P. multiflorum as an inhibitor on inflammation-related factors in human hepatoma cells. Therefore, we suggest that the roots of P. multiflorum can be used to treat natural inflammatory diseases. SUMMARY This study presented that fifteen compounds (1-15) isolated from the roots of Polygonum multiflrum exert signifiant anti inflmmatory effects by inhibiting TNF α induced NF κB activation and PPARs transcription. Abbreviation used: NF κB: Nuclear factor kappa B, PPARs: Peroxisome proliferator activated receptors, PPREs: Peroxisome proliferator response elements, TNF α: Tumor necrosis factor α, ESI-MS: Electrospray ionization mass spectrometry, HepG2: Human hepatoma cells PMID:27019559

  11. ACTIVATION ASSAY FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR- ALPHA (PPARÁ) BY PERFLUOROALKYL ACIDS (PFAAS) IN COS-1 CELLS

    EPA Science Inventory

    PFAAs have been found to elicit various physiological effects including peroxisome proliferation, indicating the mechanism of action for these chemicals could involve PPAR. This study investigates the ability of PFAAs to bind and activate mouse and human PPARα in COS-1 cell...

  12. Peroxisome proliferator-activated receptor gamma (PPARG) rs1801282 C>G polymorphism is associated with cancer susceptibility in asians: an updated meta-analysis

    PubMed Central

    Wang, Yafeng; Chen, Yu; Jiang, Heping; Tang, Weifeng; Kang, Mingqiang; Liu, Tianyun; Guo, Zengqing; Ma, Zhiqiang

    2015-01-01

    Peroxisome proliferator-activated receptor gamma (PPARG) is related to inflammation and plays an important role in the development of cancer. PPARG rs1801282 C>G polymorphism might influence the risk of cancer by regulating production of PPARG gene. Hence, a comprehensive meta-analysis was conducted to explore the association of PPARG rs1801282 C>G polymorphism with cancer susceptibility. An extensive search of PubMed and Embase databases for all relevant publications was carried out. A total of 38 publications with 16,844 cancer cases and 23,736 controls for PPARG rs1801282 C>G polymorphism were recruited in our study. Our results indicated that PPARG rs1801282 C>G variants were associated with an increased cancer risk in Asian populations and gastric cancer. In summary, the findings suggest that PPARG rs1801282 C>G polymorphism may play a crucial role in malignant transformation and the development of cancer. PMID:26550180

  13. Dissecting the role of peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in colon, breast, and lung carcinogenesis

    PubMed Central

    Foreman, Jennifer E.; Gonzalez, Frank J.

    2011-01-01

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a promising drug target since its agonists increase serum high-density lipoprotein; decrease low-density lipoprotein, triglycerides, and insulin associated with metabolic syndrome; improve insulin sensitivity; and decrease high fat diet-induced obesity. PPARβ/δ agonists also promote terminal differentiation and elicit anti-inflammatory activities in many cell types. However, it remains to be determined whether PPARβ/δ agonists can be developed as therapeutics because there are reports showing either pro- or anti-carcinogenic effects of PPARβ/δ in cancer models. This review examines studies reporting the role of PPARβ/δ in colon, breast, and lung cancers. The prevailing evidence would suggest that targeting PPARβ/δ is not only safe but could have anti-carcinogenic protective effects. PMID:22037942

  14. Down syndrome critical region 2 protein inhibits the transcriptional activity of peroxisome proliferator-activated receptor {beta} in HEK293 cells

    SciTech Connect

    Song, Hae Jin; Park, Joongkyu; Seo, Su Ryeon; Kim, Jongsun; Paik, Seung R.; Chung, Kwang Chul

    2008-11-21

    Down syndrome is mainly caused by a trisomy of chromosome 21. The Down syndrome critical region 2 (DSCR2) gene is located within a part of chromosome 21, the Down syndrome critical region (DSCR). To investigate the function of DSCR2, we sought to identify DSCR2-interacting proteins using yeast two-hybrid assays. A human fetal brain cDNA library was screened, and DSCR2 was found to interact with a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptor {beta}, (PPAR{beta}). A co-immunoprecipitation assay demonstrated that DSCR2 physically interacts with PPAR{beta} in mammalian HEK293 cells. DSCR2 also inhibited the ligand-induced transcriptional activity of PPAR{beta}. Furthermore, PPAR{beta} also decreased the solubility of DSCR2, which increased levels of insoluble DSCR2.

  15. Synthesis of N-(5-chloro-6-(quinolin-3-yloxy)pyridin-3-yl)benzenesulfonamide derivatives as non-TZD peroxisome proliferator-activated receptor γ (PPARγ) agonist.

    PubMed

    Bajare, Swapnil; Anthony, Jessy; Nair, Amrutha; Marita, Rosalind; Damre, Anagha; Patel, Dharmeshkumar; Rao, Chandrika; Sivaramakrishnan, H; Deka, Nabajyoti

    2012-12-01

    The thiazolidinediones (TZDs) are a class of oral antidiabetic drugs that improve insulin sensitivity in patients with type 2 diabetes. Although the mechanism by which the TZDs lower insulin resistance is unclear, they are known to target the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor. Ligands for PPARγ regulate adipocyte production and secretion of fatty acids as well as glucose metabolism, resulting in increased insulin sensitivity in adipose tissue, liver, and skeletal muscle. However, TZDs have several adverse effects, including weight gain and liver toxicity. Herein we report identification of non-TZD PPARγ agonists which exhibit beneficial effects similar to that of TZDs in animal models, but without the associated adverse effects.

  16. Biological evaluation and structural insights for design of subtype-selective peroxisome proliferator activated receptor-α (PPAR-α) agonists.

    PubMed

    Gangwal, Rahul P; Damre, Mangesh V; Das, Nihar R; Sharma, Shyam S; Sangamwar, Abhay T

    2015-01-15

    Peroxisome proliferator activated receptors-α (PPAR-α) control the expression of several genes involved in diseases like diabetes, hyperlipidaemia, and inflammatory disorders. Herein, we report the biological evaluation of recently identified hits from pharmacophore based virtual screening. The most potent hits, ZINC17167211, ZINC06472206 and ZINC08438472 showed EC50 values of 0.16, 1.1 and 12.1nM in PPAR-α agonist assay, respectively. Further, comparative docking and molecular dynamics analysis of selective PPAR-α agonists revealed that Thr279, Ala333, Lys358 and Met325 residues play an important role in the selective PPAR-α agonistic activity. The insights from docking and molecular dynamic studies will serve as a guideline for the development of potent and selective PPAR-α agonists.

  17. Molecular cloning and tissue distribution of peroxisome proliferator-activated receptor-alpha (PPARα) and gamma (PPARγ) in the pigeon (Columba livia domestica).

    PubMed

    Xie, P; Yuan, C; Wang, C; Zou, X-T; Po, Z; Tong, H-B; Zou, J-M

    2014-01-01

    1. Peroxisome proliferator-activated receptors (PPAR) are involved in lipid metabolism through transcriptional regulation of target gene expression. The objective of the current study was to clone and characterise the PPARα and PPARγ genes in pigeon. 2. The full-length of 1941-bp PPARα and 1653-bp PPARγ were cloned from pigeons. The two genes were predicted to encode 468 and 475 amino acids, respectively. Both proteins contained two C4-type zinc fingers, a nuclear hormone receptor DNA-binding region signature and a HOLI domain (ligand binding domain of hormone receptors), and had high identities with other corresponding avian genes. 3. Using quantitative real-time PCR, pigeon PPARα gene expression was shown to be high in kidney, liver, gizzard and duodenum whereas PPARγ was predominantly expressed in adipose tissue.

  18. Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats.

    PubMed

    Tanaka, T; Kohno, H; Yoshitani, S; Takashima, S; Okumura, A; Murakami, A; Hosokawa, M

    2001-03-15

    The biological role of the peroxisome proliferator-activated receptors (PPARs) in various diseases, including inflammation and cancer, has been highlighted recently. Although PPARgamma ligands have been found to inhibit mammary carcinogenesis in rodents, the effects on colon tumorigenesis are controversial. In the present study, three different experiments were conducted to investigate the modifying effects of PPARs ligands (PPARalpha and PPARgamma) on colitis and an early phase of colitis-related colon carcinogenesis in male F344 rats. In the first experiment, gastric gavage of troglitazone (PPARgamma ligand, 10 or 100 mg/kg body weight) or bezafibrate (PPARalpha ligand, 10 or 100 mg/kg body weight) inhibited colitis induced by dextran sodium sulfate (DSS) and lowered trefoil factor-2 content in colonic mucosa. In the second experiment, dietary administration (0.01 or 0.05% in diet) of troglitazone and bezafibrate for 4 weeks significantly reduced azoxymethane (AOM, two weekly s.c. injections, 20 mg/kg body weight)-induced formation of aberrant crypts foci, which are precursor lesions for colon carcinoma. In the third experiment, dietary administration (0.01% in diet for 6 weeks) of pioglitazone (PPARgamma ligand), troglitazone, and bezafibrate effectively suppressed DSS/AOM-induced ACF. Administration of both ligands significantly reduced cell proliferation activity in colonic mucosa exposed to DSS and AOM. Our results suggest that synthetic PPARs ligands (PPARalpha and PPARgamma) can inhibit the early stages of colon tumorigenesis with or without colitis.

  19. Hepatic peroxisome proliferator-activated receptor γ and α-mRNA expression in HCV-infected adults is decreased by HIV co-infection and is also affected by ethnicity

    PubMed Central

    Shores, Nathan J; Mendes-Corrêa, Maria Cássia; Maida, Ivana; Turner, JoLyn; High, Kevin P; Babudieri, Sergio; Núñez, Marina

    2015-01-01

    OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients. PMID:26735218

  20. In vitro Screening and Evaluation of 37 Traditional Chinese Medicines for Their Potential to Activate Peroxisome Proliferator-Activated Receptors-γ

    PubMed Central

    Gao, Die; Zhang, Yonglan; Yang, Fengqing; Lin, Yexin; Zhang, Qihui; Xia, Zhining

    2016-01-01

    Background: Peroxisome proliferator-activated receptors (PPAR)-γ is widely used as an attractive target for the treatment of type 2 diabetes mellitus. Thiazolidinediones, the agonists of PPARγ, has been popularly utilized as insulin sensitizers in the therapy of type 2 diabetes whereas numerous severe side-effects may also occur concomitantly. Objective: The PPARγ activation activity of different polar extracts, including petroleum ether, ethyl acetate, n-butanol, residual of ethanol, the precipitate part of water and the supernatant of water extracts, from 37 traditional Chinese medicines were systematically evaluated. Materials and Methods: HeLa cells were transiently co-transfected with the re-constructed plasmids of GAL4-PPARγ-ligand binding domain and pGL4.35. The activation of PPARγ by different polarity extracts were evaluated based on the PPARγ transactivation assay and rosiglitazone was used as positive control. Results: Seven medicines (root bark of Lycium barbarum, Anoectochilus sroxburghii, the rhizome of Phragmites australis, Pterocephalus hookeri, Polygonatum sibiricum, fruit of Gleditsia sinensis, and Epimedium brevicornu) were able to significantly activate PPARγ. Conclusion: As seven medicines were able to activate PPARγ, the anti-diabetic activity of them is likely to be mediated by this nuclear receptor. SUMMARY Lots of the tested medicinal products had activation effects on activating PPARγEthyl acetate extracts of root bark of L.barbarum, rhizome of P.saustralis and fruit of G.siasinensis showed good PPARγ activation effect similar or higher than that of positive control, 0.5 μg/mL rosiglitazonePetroleum ether extracts of A.roxburghii, P. hookeri, P. sibiricum, E.brevicornu also can significantly activate PPARγ, the effects of them were higher than t0.5 μg/mL rosiglitazoneSchisandra chinensis (Turcz.) Baill., the fruit Cornus officinalis Siebold and Zucc., Alisma plantago-aquatica L. and the root of Trichosanthes Kirilowii Maxim

  1. Monosodium glutamate neonatal intoxication associated with obesity in adult stage is characterized by chronic inflammation and increased mRNA expression of peroxisome proliferator-activated receptors in mice.

    PubMed

    Roman-Ramos, Ruben; Almanza-Perez, Julio C; Garcia-Macedo, Rebeca; Blancas-Flores, Gerardo; Fortis-Barrera, Angeles; Jasso, Edgar I; Garcia-Lorenzana, Mario; Campos-Sepulveda, Alfonso E; Cruz, Miguel; Alarcon-Aguilar, Francisco J

    2011-06-01

    The monosodium glutamate (MSG) neonatal administration in mice provides a model of obesity with impaired glucose tolerance (IGT) and insulin resistance. However, the inflammatory profile of cytokines produced from fat tissue and its relationship to the metabolic dysfunction induced by MSG have not yet been revealed. The aim of this study was to establish the inflammatory profile attributed to MSG by measuring the expression of adipokines in visceral fat and serum of 19-week-old mice as well as the peroxisome proliferator-activated receptors alpha and gamma (PPARα and γ). Some metabolic and biochemical parameters were also quantified. The MSG increased mRNA expression of interleukin-6 (IL-6), tumour necrosis factor-alpha (TNFα), resistin and leptin, but adiponectin did not exhibit any changes. In addition, impaired glucose tolerance, increased levels of insulin, resistin and leptin were observed in serum. Both PPARα and PPARγ were activated in MSG-induced obese mice, which might explain its inflammatory profile. However, liver transaminases were severely depressed, indicating that MSG may also induce liver injury, contributing to inflammation. The MSG neonatal neuro-intoxication in mice may thus provide a model of obesity and inflammation characterized by the dual activation of PPARα and PPARγ, which might offer new insights into the mechanism of inflammatory diabetes in obesity leading to steatohepatitis, as well as a suitable model to study the role of new therapeutic agents to prevent or reduce insulin resistance, the inflammatory state and liver steatosis.

  2. EPI-001 is a selective peroxisome proliferator-activated receptor-gamma modulator with inhibitory effects on androgen receptor expression and activity in prostate cancer

    PubMed Central

    Brand, Lucas J.; Olson, Margaret E.; Ravindranathan, Preethi; Guo, Hong; Kempema, Aaron M.; Andrews, Timothy E.; Chen, Xiaoli; Raj, Ganesh V.; Harki, Daniel A.; Dehm, Scott M.

    2015-01-01

    The androgen receptor (AR) is a driver of prostate cancer (PCa) cell growth and disease progression. Therapies for advanced PCa exploit AR dependence by blocking the production or action of androgens, but these interventions inevitably fail via multiple mechanisms including mutation or deletion of the AR ligand binding domain (LBD). Thus, the development of new inhibitors which act through non-LBD interfaces is an unmet clinical need. EPI-001 is a bisphenol A-derived compound shown to bind covalently and inhibit the AR NH2-terminal domain (NTD). Here, we demonstrate that EPI-001 has general thiol alkylating activity, resulting in multilevel inhibitory effects on AR in PCa cell lines and tissues. At least one secondary mechanism of action associated with AR inhibition was found to be selective modulation of peroxisome proliferator activated receptor-gamma (PPARγ). These multi-level effects of EPI-001 resulted in inhibition of transcriptional activation units (TAUs) 1 and 5 of the AR NTD, and reduced AR expression. EPI-001 inhibited growth of AR-positive and AR-negative PCa cell lines, with the highest sensitivity observed in LNCaP cells. Overall, this study provides new mechanistic insights to the chemical biology of EPI-001, and raises key issues regarding the use of covalent inhibitors of the intrinsically unstructured AR NTD. PMID:25669987

  3. Differential Roles of Peroxisome Proliferator-Activated Receptor-α and Receptor-γ on Renal Crystal Formation in Hyperoxaluric Rodents.

    PubMed

    Taguchi, Kazumi; Okada, Atsushi; Hamamoto, Shuzo; Unno, Rei; Kobayashi, Takahiro; Ando, Ryosuke; Tozawa, Keiichi; Gao, Bing; Kohri, Kenjiro; Yasui, Takahiro

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) and related inflammatory and oxidative molecule expression were investigated in a hyperoxaluric rodent model to evaluate the in vivo efficacy of PPAR agonists in preventing renal crystal formation. PPAR expression was examined in a mouse hyperoxaluria kidney stone model induced by daily intra-abdominal glyoxylate injection. Therapeutic effects of the PPARα agonist fenofibrate and PPARγ agonist pioglitazone were also assessed in a 1% ethylene glycol-induced rat model of hyperoxaluria. Crystal formation, inflammation, cell injury, apoptosis, and oxidative stress were compared to those of vehicle-treated controls. Quantitative reverse transcription-polymerase chain reaction revealed that PPARα and PPARγ expression decrease and increase, respectively, during crystal formation in hyperoxaluric kidneys. In addition, PPARα localized to the cytoplasm of both proximal and distal tubular cells, whereas PPARγ accumulated in the nucleus of proximal tubular cells. Furthermore, renal crystal formation was significantly less prevalent in pioglitazone-treated rats but higher in the fenofibrate-treated and fenofibrate/pioglitazone-cotreated groups compared to controls, thus indicating that pioglitazone, but not fenofibrate, markedly decreased cell inflammation, oxidative stress, and apoptosis. Collectively, the results demonstrated that PPARγ suppressed renal crystal formation via its antioxidative and anti-inflammatory effects; however, the renotoxicity of PPARα may elicit the opposite effect. PMID:27022389

  4. Differential Roles of Smad1 and p38 Kinase in Regulation of Peroxisome Proliferator-activating Receptor γ during Bone Morphogenetic Protein 2-induced Adipogenesis

    PubMed Central

    Hata, Kenji; Nishimura, Riko; Ikeda, Fumiyo; Yamashita, Kenji; Matsubara, Takuma; Nokubi, Takashi; Yoneda, Toshiyuki

    2003-01-01

    Bone morphogenetic protein 2 (BMP2) promotes the differentiation of undifferentiated mesenchymal cells into adipocytes. To investigate the molecular mechanisms that regulate this differentiation process, we studied the relationship between BMP2 signaling and peroxisome proliferator-activating receptor γ (PPARγ) during adipogenesis of mesenchymal cells by using pluripotent mesenchymal cell line C3H10T1/2. In C3H10T1/2 cells, BMP2 induced expression of PPARγ along with adipogenesis. Overexpression of Smad6, a natural antagonist for Smad1, blocked PPARγ expression and adipocytic differentiation induced by BMP2. Overexpression of dominant-negative PPARγ also diminished adipocytic differentiation of C3H10T1/2 cells, suggesting the central role of PPARγ in BMP2-induced adipocytic differentiation. Specific inhibitors for p38 kinase inhibited BMP2-induced adipocytic differentiation and transcriptional activation of PPARγ, whereas overexpression of Smad6 had no effect on transcriptional activity of PPARγ. Furthermore, activation of p38 kinase by overexpression of TAK1 and TAB1, without affecting PPARγ expression, led the up-regulation of transcriptional activity of PPARγ. These results suggest that both Smad and p38 kinase signaling are concomitantly activated and responsible for BMP2-induced adipocytic differentiation by inducing and up-regulating PPARγ, respectively. Thus, BMP2 controls adipocytic differentiation by using two distinct signaling pathways that play differential roles in this process in C3H10T1/2 cells. PMID:12589053

  5. Septin4_i1 Regulates Apoptosis in Hepatic Stellate Cells through Peroxisome Proliferator-Activated Receptor-γ/Akt/B-Cell Lymphoma 2 Pathway

    PubMed Central

    Zhu, Dandan; Wang, Jianxin; Sun, Xiaolei; Chen, Jinling; Pan, Jing; Xu, Tianhua; Qin, Yongwei; He, Xingxin; Huang, Caiqun

    2015-01-01

    Apoptosis of activated hepatic stellate cells (HSCs) has been verified as a potential mechanism to aid in hepatic fibrosis remission. Earlier research suggests that Septin4_i1 may sensitize hepatocellular carcinoma cells to serum starvation-induced apoptosis. Here, we aimed to investigate the effect of Septin4_i1 on HSC apoptosis and explore the associated signaling pathways. We found that Septin4_i1 can induce apoptosis in LX-2 cells and that this is accompanied by an up-regulation in cleaved-caspase-3 and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and a down-regulation in α-SMA expression. Over-expression of Septin4_i1 reduced phosphorylated Akt and B-cell lymphoma 2 (Bcl-2) expression but had no effect on the expression of p53 and death receptor (DR)-5. The decreased expression of Bcl-2 and the increased expression of cleaved-caspase-3 induced by Sept4_i1 could be reversed by GW501516, a PPAR-β/δ agonist that has been reported by others to enhance Akt signaling. In addition, GW9662, an antagonist of PPAR-γ, could also inhibit apoptosis in LX-2 cells induced by Sept4_i1. In conclusion, our data suggest that Sept4_i1 induces HSC apoptosis by inhibiting Akt and Bcl-2 expression and up-regulating PPAR-γ expression. PMID:25527525

  6. Constitutive active/androstane receptor, peroxisome proliferator-activated receptor α, and cytotoxicity are involved in oxadiazon-induced liver tumor development in mice.

    PubMed

    Kuwata, Kazunori; Inoue, Kaoru; Ichimura, Ryohei; Takahashi, Miwa; Kodama, Yukio; Yoshida, Midori

    2016-02-01

    Oxadiazon (OX) is a protoporphyrinogen oxidase-inhibiting herbicide that induces porphyria and liver tumors in rodents. Although porphyria is generally considered to be a risk factor for liver tumor development, the mechanisms through which OX mediates tumor development are unclear. Therefore, in this study, we investigated the mechanisms of tumor development by focusing on constitutive active/androstane receptor (CAR), which is essential for the development of tumors in response to several chemicals. After 1, 4, or 13 weeks of dietary treatment with 1000 ppm OX, hepatic Cyp2b10 expression was induced in wild-type (WT) mice. However, this effect was blocked in CAR-knockout (CARKO) mice. Hepatic Cyp4a10 expression, indicative of peroxisome proliferator-activated receptor α (PPARα) activation, and cytotoxic changes in hepatocytes were also observed in both groups of mice. After initiation by diethylnitrosamine, 26-week treatment with OX resulted in an increase in proliferative lesions, including foci and adenomas, in both genotypes, and the incidence and multiplicity of proliferative lesions in CARKO mice were higher than those in control mice but lower than those in WT mice. These results suggested that CAR, PPARα activation, and cytotoxicity were involved in the development of liver tumors. Moreover, porphyrin was not apparently involved in OX-induced tumor development.

  7. Septin4_i1 regulates apoptosis in hepatic stellate cells through peroxisome proliferator-activated receptor-γ/Akt/B-cell lymphoma 2 pathway.

    PubMed

    Zhu, Dandan; Wang, Jianxin; Sun, Xiaolei; Chen, Jinling; Duan, Yinong; Pan, Jing; Xu, Tianhua; Qin, Yongwei; He, Xingxin; Huang, Caiqun

    2015-03-01

    Apoptosis of activated hepatic stellate cells (HSCs) has been verified as a potential mechanism to aid in hepatic fibrosis remission. Earlier research suggests that Septin4_i1 may sensitize hepatocellular carcinoma cells to serum starvation-induced apoptosis. Here, we aimed to investigate the effect of Septin4_i1 on HSC apoptosis and explore the associated signaling pathways. We found that Septin4_i1 can induce apoptosis in LX-2 cells and that this is accompanied by an up-regulation in cleaved-caspase-3 and peroxisome proliferator-activated receptor-γ (PPAR-γ) expression and a down-regulation in α-SMA expression. Over-expression of Septin4_i1 reduced phosphorylated Akt and B-cell lymphoma 2 (Bcl-2) expression but had no effect on the expression of p53 and death receptor (DR)-5. The decreased expression of Bcl-2 and the increased expression of cleaved-caspase-3 induced by Sept4_i1 could be reversed by GW501516, a PPAR-β/δ agonist that has been reported by others to enhance Akt signaling. In addition, GW9662, an antagonist of PPAR-γ, could also inhibit apoptosis in LX-2 cells induced by Sept4_i1. In conclusion, our data suggest that Sept4_i1 induces HSC apoptosis by inhibiting Akt and Bcl-2 expression and up-regulating PPAR-γ expression. PMID:25527525

  8. Candesartan cilexetil prevents diet-induced insulin resistance via peroxisome proliferator-activated receptor-γ activation in an obese rat model

    PubMed Central

    YAN, WEN-HUA; PAN, CHANG-YU; DOU, JING-TAO; MENG, JUN-HUA; WANG, BAO-AN; MU, YI-MING

    2016-01-01

    Angiotensin II type 1 receptor (AT1R) blockers (ARBs) have been shown to reduce the incidence of type 2 diabetes mellitus; however, the underlying molecular mechanism is unknown. Peroxisome proliferator-activated receptor γ (PPARγ) is the central regulator of insulin and glucose metabolism, which improves insulin sensitivity. Whether candesartan cilexetil, as a prodrug of the AT1R blocker candesartan, has PPARγ-activating properties remains to be elucidated. The aim of the present study was to investigate the effects of oral administration of candesartan cilexetil on glucose tolerance and the actions of PPARγ on liver and adipose tissue in the insulin-resistant obese rat induced by high-fat diet. Animals treated with candesartan cilexetil showed an improved glucose tolerance after oral glucose challenge. Whole-body insulin sensitivity was evaluated using the hyperinsulinemic-euglycemic clamp technique. During high-fat feeding in high-fat diet (HF) rats, the glucose infusion rate (GIR) was 52.3% lower than that in normal chow (NC) rats. However, the GIR was significantly enhanced following candesartan cilexetil treatment. Angiotensin II receptor antagonism also resulted in significant increases in PPARγ protein expression in adipose and liver tissue. These results indicate that PPARγ activation by candesartan cilexetil may provide novel therapeutic options in the treatment of patients with metabolic syndrome. PMID:27347049

  9. Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats

    PubMed Central

    Lysne, Vegard; Strand, Elin; Svingen, Gard F. T.; Bjørndal, Bodil; Pedersen, Eva R.; Midttun, Øivind; Olsen, Thomas; Ueland, Per M.; Berge, Rolf K.; Nygård, Ottar

    2016-01-01

    Plasma concentrations of metabolites along the choline oxidation pathway have been linked to increased risk of major lifestyle diseases, and peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of key enzymes along this pathway. In this study, we investigated the effect of PPAR activation on circulating and urinary one-carbon metabolites as well as markers of B-vitamin status. Male Wistar rats (n = 20) received for 50 weeks either a high-fat control diet or a high-fat diet with tetradecylthioacetic acid (TTA), a modified fatty acid and pan-PPAR agonist with high affinity towards PPARα. Hepatic gene expression of PPARα, PPARβ/δ and the enzymes involved in the choline oxidation pathway were analyzed and concentrations of metabolites were analyzed in plasma and urine. TTA treatment altered most biomarkers, and the largest effect sizes were observed for plasma concentrations of dimethylglycine, nicotinamide, methylnicotinamide, methylmalonic acid and pyridoxal, which were all higher in the TTA group (all p < 0.01). Hepatic Pparα mRNA was increased after TTA treatment, but genes of the choline oxidation pathway were not affected. Long-term TTA treatment was associated with pronounced alterations on the plasma and urinary concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. PMID:26742069

  10. Activation of peroxisome proliferator-activated receptor-α (PPARα) in proximal intestine improves postprandial lipidemia in obese diabetic KK-Ay mice.

    PubMed

    Kimura, Rino; Takahashi, Nobuyuki; Goto, Tsuyoshi; Murota, Kaeko; Kawada, Teruo

    2013-01-01

    Postprandial lipidemia is a risk factor for cardiovascular diseases. Thus, the suppression of postprandial lipidemia is valuable for disease management. Peroxisome proliferator-activated receptor- (PPAR ) is a key regulator in the lipid metabolism of peripheral tissues such as the liver and skeletal muscle, whose activation enhances fatty acid oxidation and decreases circulating lipid level. Recently, we have shown that bezafibrate, an agonistic compound for PPAR , suppresses post-prandial lipidemia by enhancing fatty acid oxidation in intestinal epithelial cells under physiological conditions. However, it was not elucidated whether the effect of PPAR on postprandial lipidemia is also observed under obese conditions, which change lipid metabolisms in various tissues and cells. Here, we observed that bezafibrate enhanced fatty acid oxidation in intestinal epithelial cells of obese diabetic KK-Ay mice. Bezafibrate treatment increased the mRNA expression levels of fatty acid oxidation-related genes, which are targets of PPAR , and enhanced CO2 production from [14C]-palmitic acid. The bezafibrate-treated mice showed the suppression of increasing serum triacylglyceride level after the oral administration of olive oil. Moreover, the effects of bezafibrate on mRNA expression and fatty acid oxidation were shown in only the proximal intestinal epithelial cells. These findings indicate that PPAR activation suppresses postprandial lipidemia under obese conditions through the enhancement of fatty acid oxidation, and that only the proximal intestine con-tributes to the effects in mice, suggesting that intestinal PPAR can be a target for prevention of obese-induced postprandial lipidemia.

  11. Peroxisome Proliferator-Activated Receptor α Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

    PubMed Central

    Jen, Hsu-Lung; Liu, Po-Len; Chen, Jaw-Wen; Lin, Shing-Jong

    2016-01-01

    Peroxisome proliferator-activated receptor α (PPARα) plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1-) caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs) were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK) and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB) by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy. PMID:27807394

  12. Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction.

    PubMed

    Ibarra-Lara, María de la Luz; Sánchez-Aguilar, María; Soria, Elizabeth; Torres-Narváez, Juan Carlos; Del Valle-Mondragón, Leonardo; Cervantes-Pérez, Luz Graciela; Pérez-Severiano, Francisca; Ramírez-Ortega, Margarita Del Carmen; Pastelín-Hernández, Gustavo; Oidor-Chan, Víctor Hugo; Sánchez-Mendoza, Alicia

    2016-06-01

    Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1β, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

  13. Peroxisome proliferator-activated receptor γ regulates genes involved in insulin/insulin-like growth factor signaling and lipid metabolism during adipogenesis through functionally distinct enhancer classes.

    PubMed

    Oger, Frédérik; Dubois-Chevalier, Julie; Gheeraert, Céline; Avner, Stéphane; Durand, Emmanuelle; Froguel, Philippe; Salbert, Gilles; Staels, Bart; Lefebvre, Philippe; Eeckhoute, Jérôme

    2014-01-10

    The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPAR induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPAR also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPAR utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process.

  14. Molecular Mechanism of Betaine on Hepatic Lipid Metabolism: Inhibition of Forkhead Box O1 (FoxO1) Binding to Peroxisome Proliferator-Activated Receptor Gamma (PPARγ).

    PubMed

    Kim, Dae Hyun; Lee, Bonggi; Kim, Min Jo; Park, Min Hi; An, Hye Jin; Lee, Eun Kyeong; Chung, Ki Wung; Park, June Whoun; Yu, Byung Pal; Choi, Jae Sue; Chung, Hae Young

    2016-09-14

    Betaine is a major water-soluble component of Lycium chinensis. Although there are reports about the protective effects of betaine on hepatic steatosis, the underlying mechanisms are unclear. We used db/db mice and HepG2 cells to examine the mechanism underlying betaine-mediated protection against hepatic steatosis. Here, we showed increased hepatic lipid accumulation in db/db mice, which is associated with increased activation of lipogenic transcription factors including forkhead box O1 (FoxO1) and peroxisome proliferator-activated receptor gamma (PPARγ), whereas betaine administration by oral gavage reversed these characteristics. We investigated whether betaine ameliorates hepatic steatosis by inhibiting FoxO1/PPARγ signaling in HepG2 cells. Although adenovirus-mediated FoxO1 overexpression notably increased mRNA expression levels of PPARγ and its target genes including FAS and ACC, betaine treatment reversed them. Furthermore, betaine inhibited FoxO1 binding to the PPARγ promoter and PPARγ transcriptional activity in HepG2 cells, which was previously shown to induce hepatic steatosis. We concluded that betaine ameliorates hepatic steatosis, at least in part, by inhibiting the FoxO1 binding to PPARγ and their downstream lipogenic signaling cascade. PMID:27546313

  15. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha increased apoptosis of human endometrial cancer HEC-1A cells

    PubMed Central

    Yang, Hui; Yang, Rui; Liu, Hao; Ren, Zhongqian; Wang, Cuicui; Li, Da; Ma, Xiaoxin

    2016-01-01

    Background Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) coactivates multiple transcription factors and regulates several metabolic processes. In this study, we focused on the roles of PGC-1α in the apoptosis of endometrial cancer HEC-1A cells. Materials and methods PGC-1a expression in the HEC-1A cells was detected with real-time polymerase chain reaction and Western blot. Small interfering RNA directed against PGC-1α was designed and synthesized, and RNA interference technology was used to knock down PGC-1α mRNA and protein expression. Cell apoptosis, cell cycle, and mitochondrial membrane potential were then analyzed using flow cytometry. The expression of apoptotic proteins, Bcl-2 and Bax, was detected with Western blot. Results The specific downregulation of PGC-1α expression in the HEC-1A cells increased their apoptosis through the mitochondrial apoptotic pathway by reducing the expression of Bcl-2 and increasing the expression of Bax. Conclusion These results suggest that PGC-1α influences the apoptosis of HEC-1A cells and also provides a molecular basis for further investigation of the apoptotic mechanism in human endometrial cancer.

  16. Danhong inhibits oxidized low-density lipoprotein-induced immune maturation of dentritic cells via a peroxisome proliferator activated receptor γ-mediated pathway.

    PubMed

    Liu, Hongying; Wang, Shijun; Sun, Aijun; Huang, Dong; Wang, Wei; Zhang, Chunyu; Shi, Dazhuo; Chen, Keji; Zou, Yunzeng; Ge, Junbo

    2012-01-01

    Danhong injection (DHI), a Chinese Materia Medica standardized product extracted from Radix Salviae miltiorrhizae and Flos Carthami tinctorii, is effective in the treatment of atherosclerosis (AS)-related diseases. It is widely recognized that AS is a complex inflammatory disease of the arterial wall and the dendritic cells (DCs) is a major player in the pathogenesis of AS via mediating atherosclerotic antigen presenting and T lymphocytes. Here, we determined the effect and possible mechanism of DHI on oxidized low-density lipoprotein (ox-LDL)-induced maturation and immune function of DCs. Human monocyte-derived DCs were incubated with DHI or ciglitazone and were subsequently stimulated with ox-LDL to induce maturation. Similar to ciglitazone, a peroxisome proliferator activated receptor (PPAR) γ agonist, DHI, could significantly reduce ox-LDL-induced expressions of mature markers, enhance the endocytotic function, and inhibit secretions of cytokine on DCs. These effects of DHI could be partly reversed by silencing the PPARγ. In conclusion, DHI could inhibit ox-LDL-induced maturation of DCs partly through activating a PPARγ-mediated signaling pathway.

  17. Activation of Human Peroxisome Proliferator-Activated Nuclear Receptors (PPARγ1) by Semi-Volatile Compounds (SVOCs) and Chemical Mixtures in Indoor Dust.

    PubMed

    Fang, Mingliang; Webster, Thomas F; Stapleton, Heather M

    2015-08-18

    Recently, we reported that several semi-volatile compounds (SVOCs) were competitive ligands for human peroxisome proliferator-activated nuclear receptor gamma (PPARγ1). We also observed significant binding from chemicals extracted from house dust at a concentration of 3 mg dust/mL in the dosing medium. To follow up on this study, a commercially available reporter gene assay (GeneBLAzer PPARγ1 non-DA Assay, Invitrogen) was used to investigate the PPARγ1 activation by 30 common SVOCs (e.g., brominated flame retardants, organophosphates, and phthalates) and in house dust extracts. Twenty-eight SVOCs or their metabolites were either confirmed or for the first time were found to be weak or moderate PPARγ1 agonists. We also observed activation in 15 of 25 dust extracts examined. In some cases, activation was as high as 50% of the activation of the positive control (rosiglitazone). Furthermore, there was a significant and positive correlation (r = 0.7, p < 0.003) between data collected from this reporter assay and our previous ligand binding assay tested on the same dust extracts. Our results suggest that many SVOCs ubiquitous in house dust, or their metabolites, are possible PPARγ1 agonists. Also, chemical mixtures present in house dust at environmentally relevant levels can activate human PPARγ1 in a transfected cell culture system, and further research is needed to identify the primary chemical(s) driving this activity. PMID:26172262

  18. Differential transcriptional activation of peroxisome proliferator-activated receptor gamma by omega-3 and omega-6 fatty acids in MCF-7 cells.

    PubMed

    Thoennes, S R; Tate, P L; Price, T M; Kilgore, M W

    2000-02-25

    While the role of dietary fats in breast cancer remains controversial, the recent cloning of peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor, from human breast cancer cells lines provides a potential molecular link. Several fatty acids from four classes of dietary fats were tested for their ability to mediate the transcriptional activity of PPARgamma in MCF-7 and MDA-MB-231 cells using growth media with minimal serum. Whereas omega-3 fatty acids inhibit transactivation of PPARgamma to levels below control, omega-6, monounsaturated and saturated fatty acids stimulate the activity of the transcriptional reporter. These studies indicate that individual fatty acids differentially regulate the transcriptional activity of PPARgamma by selectively acting as agonists or antagonists. Furthermore, the transcriptional activation of PPARgamma correlates with cell proliferation in MCF-7 cells. Understanding the effects of individual fats on breast cancer cells and PPARgamma transactivation could provide important new insights into the epidemiology of breast cancer and the role of dietary fat.

  19. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells.

    PubMed

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA-PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  20. Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

    PubMed

    Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélén; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Saati, Talal Al; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

    2014-01-01

    Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers. PMID:24203162

  1. Over-expression of C/EBP-{alpha} induces apoptosis in cultured rat hepatic stellate cells depending on p53 and peroxisome proliferator-activated receptor-{gamma}

    SciTech Connect

    Wang Xueqing; Huang Guangcun; Mei Shuang; Qian Jin; Ji Juling; Zhang Jinsheng

    2009-03-06

    Hepatic stellate cells (HSCs) play a key role in the pathogenesis of hepatic fibrosis. In our previous studies, CCAAT enhancer binding protein-{alpha} (C/EBP-{alpha}) has been shown to be involved in the activation of HSCs and to have a repression effect on hepatic fibrosis in vivo. However, the mechanisms are largely unknown. In this study, we show that the infection of adenovirus vector expressing C/EBP-{alpha} gene (Ad-C/EBP-{alpha}) could induce HSCs apoptosis in a dose- and time-dependent manner by Annexin V/PI staining, caspase-3 activation assay, and flow cytometry. Also, over-expression of C/EBP-{alpha} resulted in the up-regulation of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) and P53, while P53 expression was regulated by PPAR-{gamma}. In addition, Fas, FasL, DR4, DR5, and TRAIL were studied. The results indicated that the death receptor pathway was mainly involved and regulated by PPAR-{gamma} and p53 in the process of apoptosis triggered by C/EBP-{alpha} in HSCs.

  2. The effects of Musk T on peroxisome proliferator-activated receptor [PPAR]-alpha activation, epidermal skin homeostasis and dermal hyaluronic acid synthesis.

    PubMed

    Kim, Seung Hun; Nam, Gae Won; Lee, Hae Kwang; Moon, Seong Joon; Chang, Ih Seop

    2006-11-01

    Peroxisome proliferators activated receptors (PPARs) are a family of nuclear hormone receptors that heterodimer with the retinoid X receptor and function as transcriptional regulators of genes. Topically Applied PPAR-alpha agonists possess receptor mediated, pro-differentiating/anti-proliferative effects, lipid metabolism stimulation, and anti-inflammatory activity, which suggest that they could be beneficial for the treatment of a variety of cutaneous diseases. Hyaluronan (HA), a high-molecular-weight linear glycosaminoglycan consisting of alternating D: -glucuronic acid and N-acetyl-D: -glucosamine residues, is one of the major extracellular matrix components in skin. Among the family of HA synthase genes (HAS1, 2, 3) so far identified, one group has demonstrated that the expressions of HAS2 and HAS3 play crucial roles in the regulation of HA synthesis in human skin fibroblasts and keratinocytes, respectively, but the precise regulatory mechanisms are still unknown. We examine Musk T called Ethylene brassylate, Astratone or 1,4-Dioxacycloheptadecane-5,17-dione, which used as just a perfume ingredient, plays a role as PPAR-alpha ligand in vitro and stimulates skin barrier recovery, ceramide synthesis, beta-Glucocerebrosidase, involucrin expression in epidermis in vivo; and examine that Musk T stimulates HAS expression and HA synthesis in human skin fibroblast. Through these experiments, we conclude that Musk T is PPAR-alpha ligand, effects on keratinocyte differentiation, intercellular lipid synthesis in epidermis, HA synthesis stimulation in dermis.

  3. Increased peroxisome proliferator-activated receptor γ expression levels in visceral adipose tissue, and serum CCL2 and interleukin-6 levels during visceral adipose tissue accumulation.

    PubMed

    Yogarajah, Thaneswary; Bee, Yvonne-Tee Get; Noordin, Rahmah; Yin, Khoo Boon

    2015-01-01

    This study was conducted to determine the mRNA and protein expression levels of peroxisome proliferator-activated receptors (PPARs) in visceral adipose tissue, as well as serum adipokine levels, in Sprague Dawley rats. The rats were fed either a normal (control rats) or excessive (experimental rats) intake of food for 8 or 16 weeks, then sacrificed, at which time visceral and subcutaneous adipose tissues, as well as blood samples, were collected. The mRNA and protein expression levels of PPARs in the visceral adipose tissues were determined using reverse transcription-polymerase chain reaction and Western blotting, respectively. In addition, the levels of adipokines in the serum samples were determined using commercial ELISA kits. The results revealed that at 8 weeks, the mass of subcutaneous adipose tissue was higher than that of the visceral adipose tissue in the experimental rats, but the reverse occurred at 16 weeks. Furthermore, at 16 weeks the experimental rats exhibited an upregulation of PPARγ mRNA and protein expression levels in the visceral adipose tissues, and significant increases in the serum levels of CCL2 and interleukin (IL)-6 were observed, compared with those measured at 8 weeks. In conclusion, this study demonstrated that the PPARγ expression level was likely correlated with serum levels of CCL2 and IL-6, molecules that may facilitate visceral adipose tissue accumulation. In addition, the levels of the two adipokines in the serum may be useful as surrogate biomarkers for the expression levels of PPARγ in accumulated visceral adipose tissues.

  4. C333H ameliorated insulin resistance through selectively modulating peroxisome proliferator-activated receptor γ in brown adipose tissue of db/db mice.

    PubMed

    Zhang, Ning; Chen, Wei; Zhou, Xinbo; Zhou, Xiaolin; Xie, Xinni; Meng, Aimin; Li, Song; Wang, Lili

    2013-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a unique target for insulin sensitizer agents. These drugs have been used for the clinical treatment of type 2 diabetes for almost twenty years. However, serious safety issues are associated with the PPARγ agonist thiazolidinediones (TZDs). Selective PPARγ modulators (SPPARMs) which retain insulin sensitization without TZDs-like side effects are emerging as a promising new generation of insulin sensitizers. C333H is a novel structure compound synthesized by our laboratory. In diabetic rodent models, C333H has insulin-sensitizing and glucose-lowering activity comparable to that of TZDs, and causes no significant increase in body weight or adipose tissue weight in db/db mice. In diabetic db/db mice, C333H elevated circulating high molecular weight adiponectin isoforms, decreased PPARγ 273 serine phosphorylation in brown adipose tissue and selectively modulated the expression of a subset of PPARγ target genes in adipose tissue. In vitro, C333H weakly recruited coactivator and weakly dissociated corepressor activity. These findings suggest that C333H has similar properties to SPPARMs and may be a potential therapeutic agent for the treatment of type 2 diabetes.

  5. Lipids Derived from Virulent Francisella tularensis Broadly Inhibit Pulmonary Inflammation via Toll-Like Receptor 2 and Peroxisome Proliferator-Activated Receptor α

    PubMed Central

    Crane, Deborah D.; Ireland, Robin; Alinger, Joshua B.; Small, Pamela

    2013-01-01

    Francisella tularensis is a Gram-negative facultative intracellular pathogen that causes an acute lethal respiratory disease in humans. The heightened virulence of the pathogen is linked to its unique ability to inhibit Toll-like receptor (TLR)-mediated inflammatory responses. The bacterial component and mechanism of this inhibition are unknown. Here we show that lipids isolated from virulent but not attenuated strains of F. tularensis are not detected by host cells, inhibit production of proinflammatory cytokines by primary macrophages in response to known TLR ligands, and suppress neutrophil recruitment in vivo. We further show that lipid-mediated inhibition of inflammation is dependent on TLR2, MyD88, and the nuclear hormone and fatty acid receptor peroxisome proliferator-activated receptor α (PPARα). Pathogen lipid-mediated interference with inflammatory responses through the engagement of TLR2 and PPARα represents a novel manipulation of host signaling pathways consistent with the ability of highly virulent F. tularensis to efficiently evade host immune responses. PMID:23925884

  6. Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses.

    PubMed

    Aleshin, Stepan; Strokin, Mikhail; Sergeeva, Marina; Reiser, Georg

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARα, -β/δ and -γ) are lipid-activated transcription factors. Synthetic PPARα and PPARγ ligands have neuroprotective properties. Recently, PPARβ/δ activation emerged as the focus of a novel approach for the treatment of a wide range of neurodegenerative diseases. To fill the gap of knowledge about the role of PPARβ/δ in brain, new hypotheses about PPARβ/δ involvement in neuropathological processes are requested. In this paper, we describe a novel hypothesis, claiming the existence of tight interactions between the three PPAR isotypes, which we designate the "PPAR triad". We propose that PPARβ/δ has a central control of the PPAR triad. The majority of studies analyze the regulation only by one of the PPAR isotypes. A few reports describe the mutual regulation of expression levels of all three PPAR isotypes by PPAR agonists. Analysis of these studies where pairwise interactions of PPARs were described allows us to support the existence of the PPAR triad with central role for PPARβ/δ. In the present review, we propose the hypothesis that in a wide range of brain disorders, PPARβ/δ plays a central role between PPARα and PPARγ. Finally, we prove the advantages of the PPAR triad concept by describing hypotheses of PPARβ/δ involvement in the regulation of myelination, glutamate-induced neurotoxicity, and signaling pathways of reactive oxygen species/NO/Ca(2+). PMID:23811400

  7. Regulation of Peroxisome Proliferator-Activated Receptor γ Expression by Adipocyte Differentiation and Determination Factor 1/Sterol Regulatory Element Binding Protein 1: Implications for Adipocyte Differentiation and Metabolism

    PubMed Central

    Fajas, Lluis; Schoonjans, Kristina; Gelman, Laurent; Kim, Jae B.; Najib, Jamila; Martin, Genevieve; Fruchart, Jean-Charles; Briggs, Michael; Spiegelman, Bruce M.; Auwerx, Johan

    1999-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor implicated in adipocyte differentiation and insulin sensitivity. We investigated whether PPARγ expression is dependent on the activity of adipocyte differentiation and determination factor 1/sterol regulatory element binding protein 1 (ADD-1/SREBP-1), another transcription factor associated with both adipocyte differentiation and cholesterol homeostasis. Ectopic expression of ADD-1/SREBP-1 in 3T3-L1 and HepG2 cells induced endogenous PPARγ mRNA levels. The related transcription factor SREBP-2 likewise induced PPARγ expression. In addition, cholesterol depletion, a condition known to result in proteolytic activation of transcription factors of the SREBP family, induced PPARγ expression and improved PPRE-driven transcription. The effect of the SREBPs on PPARγ expression was mediated through the PPARγ1 and -3 promoters. Both promoters contain a consensus E-box motif that mediates the regulation of the PPARγ gene by ADD-1/SREBP-1 and SREBP-2. These results suggest that PPARγ expression can be controlled by the SREBP family of transcription factors and demonstrate new interactions between transcription factors that can regulate different pathways of lipid metabolism. PMID:10409739

  8. Differential regulation of peroxisome proliferator activated receptor gamma1 (PPARgamma1) and PPARgamma2 messenger RNA expression in the early stages of adipogenesis.

    PubMed

    Saladin, R; Fajas, L; Dana, S; Halvorsen, Y D; Auwerx, J; Briggs, M

    1999-01-01

    Adipocyte differentiation is driven by the expression and activation of three transcription factor families: the differentially expressed CAAT/enhancer binding proteins (C/EBPs) alpha, beta, and delta; the helix-loop-helix adipocyte differentiation and determination factor-1; and peroxisome proliferator activated receptor gamma (PPARgamma), expressed as two isoforms, PPARgamma1 and the adipocyte-specific PPARgamma2. Overexpression of PPARgamma can induce adipocyte differentiation; therefore, we analyzed the expression of the two PPARgamma isoforms during early stages of differentiation to determine whether one was preferentially induced as an early determining event. Surprisingly, in the first 24 h, a 3-6-fold increase of PPARgamma2 mRNA was observed, whereas PPARgamma1 mRNA remained unchanged. PPARgamma1 was induced 1 day later. Overexpression of C/EBPbeta has also been shown to induce adipocyte differentiation. A C/EBP site was identified only in the human PPARgamma2 promoter. Its deletion blunted the response of PPARgamma2 promoter to cotransfected C/EBPbeta or methylisobutylxanthine treatment. We hypothesize that PPARgamma2 initiates adipocyte differentiation.

  9. Ligand-dependent coactivation of the human bile acid receptor FXR by the peroxisome proliferator-activated receptor gamma coactivator-1alpha.

    PubMed

    Savkur, Rajesh S; Thomas, Jeffrey S; Bramlett, Kelli S; Gao, Yunling; Michael, Laura F; Burris, Thomas P

    2005-01-01

    Peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) has been shown to play an important role in energy metabolism by coordinating transcriptional programs involved in mitochondrial biogenesis, adaptive thermogenesis, gluconeogenesis, and fatty acid oxidation. PGC-1alpha also plays a crucial role in cholesterol metabolism by serving as a coactivator of the liver X receptor-alpha and inducing the expression of cholesterol 7-alpha-hydroxylase. Here, we demonstrate that PGC-1alpha also functions as an effective coactivator of farnesoid X receptor (FXR), the bile acid receptor. Transient cotransfection assays demonstrate that PGC-1alpha enhances ligand-mediated FXR transcription when either full-length FXR or Gal4 DNA binding domain-FXR-ligand binding domain chimeras were analyzed. Mammalian two-hybrid analyses, glutathione S-transferase affinity chromatography and biochemical coactivator recruitment assays demonstrate ligand-dependent interaction between the two proteins both in vivo and in vitro. PGC-1alpha-mediated coactivation of FXR was highly ligand-dependent and absolutely required an intact activation function-2 (AF-2) domain of FXR and the LXXLL motif in PGC-1alpha. The integrity of the charge clamp was required, further illustrating the role of the ligand binding domain of FXR in PGC-1alpha recognition. Together, these results indicate that PGC-1alpha functions as a potent coactivator for FXR and further implicates its role in the regulation of genes that are involved in bile acid and lipid metabolism.

  10. Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor γ agonist.

    PubMed

    Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi; Kawachi, Atsushi; Kawada, Kiyokazu; Han, Junkyu; Isoda, Hiroko; Neffati, Mohamed; Akita, Toru; Maejima, Kazuhiro; Masuda, Seiji; Kambe, Taiho; Mori, Naoki; Irie, Kazuhiro; Nagao, Masaya

    2013-10-18

    6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Fibrogenesis caused by hepatic stellate cells is inhibited by PPARγ whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPARγ agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPARγ agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPARγ in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPARγ-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPARγ agonists.

  11. The Farnesoid X Receptor Regulates Adipocyte Differentiation and Function by Promoting Peroxisome Proliferator-activated Receptor-γ and Interfering with the Wnt/β-Catenin Pathways*

    PubMed Central

    Abdelkarim, Mouaadh; Caron, Sandrine; Duhem, Christian; Prawitt, Janne; Dumont, Julie; Lucas, Anthony; Bouchaert, Emmanuel; Briand, Olivier; Brozek, John; Kuipers, Folkert; Fievet, Catherine; Cariou, Bertrand; Staels, Bart

    2010-01-01

    The bile acid receptor farnesoid X receptor (FXR) is expressed in adipose tissue, but its function remains poorly defined. Peroxisome proliferator-activated receptor-γ (PPARγ) is a master regulator of adipocyte differentiation and function. The aim of this study was to analyze the role of FXR in adipocyte function and to assess whether it modulates PPARγ action. Therefore, we tested the responsiveness of FXR-deficient mice (FXR−/−) and cells to the PPARγ activator rosiglitazone. Our results show that genetically obese FXR−/−/ob/ob mice displayed a resistance to rosiglitazone treatment. In vitro, rosiglitazone treatment did not induce normal adipocyte differentiation and lipid droplet formation in FXR−/− mouse embryonic fibroblasts (MEFs) and preadipocytes. Moreover, FXR−/− MEFs displayed both an increased lipolysis and a decreased de novo lipogenesis, resulting in reduced intracellular triglyceride content, even upon PPARγ activation. Retroviral-mediated FXR re-expression in FXR−/− MEFs restored the induction of adipogenic marker genes during rosiglitazone-forced adipocyte differentiation. The expression of Wnt/β-catenin pathway and target genes was increased in FXR−/− adipose tissue and MEFs. Moreover, the expression of several endogenous inhibitors of this pathway was decreased early during the adipocyte differentiation of FXR−/− MEFs. These findings demonstrate that FXR regulates adipocyte differentiation and function by regulating two counteracting pathways of adipocyte differentiation, the PPARγ and Wnt/β-catenin pathways. PMID:20851881

  12. The Multiple Endocrine Neoplasia Type 1 (MEN1) Tumor Suppressor Regulates Peroxisome Proliferator-Activated Receptor γ-Dependent Adipocyte Differentiation▿

    PubMed Central

    Dreijerink, Koen M. A.; Varier, Radhika A.; van Beekum, Olivier; Jeninga, Ellen H.; Höppener, Jo W. M.; Lips, Cornelis J. M.; Kummer, J. Alain; Kalkhoven, Eric; Timmers, H. T. Marc

    2009-01-01

    Menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, is involved in activation of gene transcription as part of an MLL1 (mixed-lineage leukemia 1)/MLL2 (KMT2A/B)-containing protein complex which harbors methyltransferase activity for lysine 4 of histone H3 (H3K4). As MEN1 patients frequently develop lipomas and peroxisome proliferator-activated receptor γ (PPARγ) is expressed in several MEN1-related tumor types, we investigated regulation of PPARγ activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPARγ-expressing mouse embryonic fibroblasts. Menin augments PPARγ target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPARγ in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPARγ. We propose that menin is an important factor in PPARγ-mediated adipogenesis and that loss of PPARγ function may contribute to lipoma development in MEN1 patients. PMID:19596783

  13. Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs) in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

    PubMed Central

    Laganà, Antonio Simone; Vitale, Salvatore Giovanni; Nigro, Angela; Sofo, Vincenza; Salmeri, Francesca Maria; Rossetti, Paola; Rapisarda, Agnese Maria Chiara; La Vignera, Sandro; Condorelli, Rosita Angela; Rizzo, Gianluca; Buscema, Massimo

    2016-01-01

    Background: Peroxisome proliferator-activated receptors (PPARs) have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM) and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer. PMID:27347932

  14. Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor γ and the retinoid X receptor

    PubMed Central

    Tontonoz, Peter; Singer, Samuel; Forman, Barry M.; Sarraf, Pasha; Fletcher, Jonathan A.; Fletcher, Christopher D. M.; Brun, Regina P.; Mueller, Elisabetta; Altiok, Soner; Oppenheim, Heather; Evans, Ronald M.; Spiegelman, Bruce M.

    1997-01-01

    Induction of terminal differentiation represents a promising therapeutic approach to certain human malignancies. The peroxisome proliferator-activated receptor γ (PPARγ) and the retinoid X receptor α (RXRα) form a heterodimeric complex that functions as a central regulator of adipocyte differentiation. Natural and synthetic ligands for both receptors have been identified. We demonstrate here that PPARγ is expressed at high levels in each of the major histologic types of human liposarcoma. Moreover, primary human liposarcoma cells can be induced to undergo terminal differentiation by treatment with the PPARγ ligand pioglitazone, suggesting that the differentiation block in these cells can be overcome by maximal activation of the PPAR pathway. We further demonstrate that RXR-specific ligands are also potent adipogenic agents in cells expressing the PPARγ/RXRα heterodimer, and that simultaneous treatment of liposarcoma cells with both PPARγ- and RXR-specific ligands results in an additive stimulation of differentiation. Liposarcoma cell differentiation is characterized by accumulation of intracellular lipid, induction of adipocyte-specific genes, and withdrawal from the cell cycle. These results suggest that PPARγ ligands such as thiazolidinediones and RXR-specific retinoids may be useful therapeutic agents for the treatment of liposarcoma. PMID:8990192

  15. The multiple endocrine neoplasia type 1 (MEN1) tumor suppressor regulates peroxisome proliferator-activated receptor gamma-dependent adipocyte differentiation.

    PubMed

    Dreijerink, Koen M A; Varier, Radhika A; van Beekum, Olivier; Jeninga, Ellen H; Höppener, Jo W M; Lips, Cornelis J M; Kummer, J Alain; Kalkhoven, Eric; Timmers, H T Marc

    2009-09-01

    Menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, is involved in activation of gene transcription as part of an MLL1 (mixed-lineage leukemia 1)/MLL2 (KMT2A/B)-containing protein complex which harbors methyltransferase activity for lysine 4 of histone H3 (H3K4). As MEN1 patients frequently develop lipomas and peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in several MEN1-related tumor types, we investigated regulation of PPARgamma activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPARgamma-expressing mouse embryonic fibroblasts. Menin augments PPARgamma target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPARgamma in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPARgamma. We propose that menin is an important factor in PPARgamma-mediated adipogenesis and that loss of PPARgamma function may contribute to lipoma development in MEN1 patients.

  16. Peroxisome proliferator-activated receptor δ (PPARδ) induces estrogen receptor-positive mammary neoplasia through an inflammatory and metabolic phenotype linked to mTor activation

    PubMed Central

    Yuan, Hongyan; Lu, Jin; Xiao, Junfeng; Upadhyay, Geeta; Umans, Rachel; Kallakury, Bhaskar; Yin, Yuhzi; Fant, Michael E.; Kopelovich, Levy; Glazer, Robert I.

    2013-01-01

    The peroxisome proliferator-activated receptor-δ (PPARδ) regulates a multitude of physiological processes associated with glucose and lipid metabolism, inflammation and proliferation. One or more of these processes are potential risk factors for the ability of PPARδ agonists to promote tumorigenesis in the mammary gland. In the present study, we describe a new transgenic mouse model in which activation of PPARδ in the mammary epithelium by endogenous or synthetic ligands resulted in progressive histopathological changes that culminated in the appearance of estrogen receptor- and progesterone receptor-positive and ErbB2-negative infiltrating ductal carcinomas. Multiparous mice presented with mammary carcinomas after a latency of 12 months, and administration of the PPARδ ligand GW501516 reduced tumor latency to five months. Histopathological changes occurred concurrently with an increase in an inflammatory, invasive, metabolic and proliferative gene signature, including expression of the trophoblast gene, Plac1, beginning one week after GW501516 treatment, and remained elevated throughout tumorigenesis. The appearance of malignant changes correlated with a pronounced increase in phosphatidylcholine and lysophosphatidic acid metabolites, which coincided with activation of Akt and mTor signaling that were attenuated by treatment with the mTor inhibitor everolimus. Our findings are the first to demonstrate a direct role of PPARδ in the pathogenesis of mammary tumorigenesis, and suggest a rationale for therapeutic approaches to prevent and treat this disease. PMID:23811944

  17. Antagonist of peroxisome proliferator-activated receptor {gamma} induces cerebellar amyloid-{beta} levels and motor dysfunction in APP/PS1 transgenic mice

    SciTech Connect

    Du, Jing; Sun, Bing; Chen, Kui; Fan, Li; Wang, Zhao

    2009-07-03

    Recent evidences show that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) is involved in the modulation of the amyloid-{beta} (A{beta}) cascade causing Alzheimer's disease (AD) and treatment with PPAR{gamma} agonists protects against AD pathology. However, the function of PPAR{gamma} steady-state activity in A{beta} cascade and AD pathology remains unclear. In this study, an antagonist of PPAR{gamma}, GW9662, was injected into the fourth ventricle of APP/PS1 transgenic mice to inhibit PPAR{gamma} activity in cerebellum. The results show that inhibition of PPAR{gamma} significantly induced A{beta} levels in cerebellum and caused cerebellar motor dysfunction in APP/PS1 transgenic mice. Moreover, GW9662 treatment markedly decreased the cerebellar levels of insulin-degrading enzyme (IDE), which is responsible for the cellular degradation of A{beta}. Since cerebellum is spared from significant A{beta} accumulation and neurotoxicity in AD patients and animal models, these findings suggest a crucial role of PPAR{gamma} steady-state activity in protection of cerebellum against AD pathology.

  18. Peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARβ/δ) gene expression profile on ram spermatozoa and their relation to the sperm motility.

    PubMed

    Kadivar, Ali; Heidari Khoei, Heidar; Hassanpour, Hossein; Ghanaei, Hamid; Golestanfar, Arefeh; Mehraban, Hossein; Davoodian, Najmeh; Dehghani Tafti, Roohollah

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a member of nuclear receptors superfamily, which mainly regulate the expression of target genes involved in lipid and energy metabolism. These receptors are divided to three isotypes: PPARα, PPARγ and PPARβ/δ. Each isotype has a distinct tissue distribution relating to the distinct functions. In this study, the mRNA abundance for PPARα, PPARγ and PPARβ/δ was evaluated and compared with high and low motile ram spermatozoa. Semen samples from 6 adult rams were fractionated on a two layer discontinuous Percoll gradient to high and low motile sperm and quantitative parameters of sperm motility were determined by CASA. Total RNA was extracted and the mRNA abundance for each gene was measured by relative quantification technique with Real time PCR. The levels of three isotypes of PPAR transcripts were significantly higher in high motile semen samples using quantitative RT-PCR. Some of sperm motility indices were also significantly correlated with PPARα and PPARγ relative expression. This study revealed the novel association of PPAR gene isotypes with sperm motility. Data from our study suggested PPARs are one of the possible factors that can be studied in male infertility. PMID:27226884

  19. Peroxisome proliferator-activated receptor γ attenuates serotonin-induced pulmonary artery smooth muscle cell proliferation and apoptosis inhibition involving ERK1/2 pathway.

    PubMed

    Han, Xinyuan; Chen, Chunyan; Cheng, Gong; Liang, Lei; Yao, Xiaowei; Yang, Guang; You, Penghua; Shou, Xiling

    2015-07-01

    Serotonin (5-HT) has been shown to be involved in pulmonary vascular remodeling in pulmonary arterial hypertension (PAH) by inducing pulmonary artery smooth muscle cells (PASMCs) proliferation and inhibiting PASMC apoptosis. Peroxisome proliferator-activated receptor γ (PPARγ) plays a crucial role in regulating proliferation and apoptosis of many cell types. Moreover, recently, loss of PPARγ has also been reported to be associated with the development of PAH. The present study is aimed to assess whether PPARγ is involved in 5-HT induced PASMC proliferation and apoptosis inhibition and the possible mechanism. We found that 5-HT could induce PASMC proliferation and inhibit PASMC apoptosis in a dose-dependent manner. Furthermore, we found that 5-HT negatively regulated PPARγ expression and gene promoter activity in PASMCs and 5-HT induced PASMC proliferation and apoptosis resistance could be abolished by PPARγ agonists and enhanced by PPARγ inhibitor. In addition, we found that extracellular signal-regulated kinase (ERK) signaling pathway mediated the 5-HT-induced inhibition of PPARγ expression. Our results might provide novel insights into the mechanisms for the pro-remodeling action of 5-HT in pulmonary vasculature.

  20. Caffeic Acid Inhibits UVB-induced Inflammation and Photocarcinogenesis Through Activation of Peroxisome Proliferator-activated Receptor-γ in Mouse Skin.

    PubMed

    Balupillai, Agilan; Prasad, Rajendra N; Ramasamy, Karthikeyan; Muthusamy, Ganesan; Shanmugham, Mohana; Govindasamy, Kanimozhi; Gunaseelan, Srithar

    2015-11-01

    In this study, the effect of caffeic acid (CA) on both acute and chronic UVB-irradiation-induced inflammation and photocarcinogenesis was investigated in Swiss albino mice. Animals were exposed to 180 mJ cm(-2) of UVB once daily for 10 consecutive days and thrice weekly for 30 weeks for acute and chronic study respectively. UVB exposure for 10 consecutive days showed edema formation, increased lipid peroxidation and decreased antioxidant status with activation of inflammatory molecules such as TNF-α, IL-6, COX-2 and NF-κB. However, CA (15 mg per kg.b.wt.) administration before each UVB exposure decreased lipid peroxidation, inflammatory markers expression and enhanced antioxidant status probably through the activation of peroxisome proliferator-activated receptors (PPARγ) in the mice skin. PPARγ is considered a potential target for photochemoprevention because it inhibits UVB-mediated inflammatory responses. In this study, UVB exposure for 30 weeks caused squamous cell carcinoma and upregulation of iNOS, VEGF and TGF-β and downregulation of p53 and tumor incidence in the mice skin. Both topical (CAT) and intraperitoneal (CAIP) treatment before each UVB exposure downregulates iNOS, VEGF, TGF-β, upregulates p53 and reduces tumors multiplicity in the mice skin. Thus, CA offers protection against UVB-induced photocarcinogenesis probably through activation of anti-inflammatory transcription factor PPARγ in the mice.

  1. Catalase potentiates retinoic acid-induced THP-1 monocyte differentiation into macrophage through inhibition of peroxisome proliferator-activated receptor gamma.

    PubMed

    Ding, Qiurong; Jin, Ting; Wang, Zhenzhen; Chen, Yan

    2007-06-01

    Macrophage differentiation plays a pivotal role in cardiovascular diseases and many other physiological processes. However, the role of reaction oxygen species in macrophage differentiation has not been elucidated. Here, we report functional characterization of catalase, an enzyme that degrades hydrogen peroxide (H(2)O(2)), in THP-1 monocyte differentiation. Treatment of THP-1 cells with catalase was able to synergize with all-trans retinoic acid (ATRA) to enhance macrophage differentiation, demonstrated by changes of cell adherence, cell cycle arrest, nitroblue tetrazolium reduction, and expression of differentiation markers including CD68, CD11b, and matrix metalloproteinase 9 (MMP9). ATRA could stimulate retinoic acid (RA) receptor-mediated transcription, but this was not affected by catalase. However, ATRA and catalase were capable of reducing transcriptional activity mediated by peroxisome proliferator-activated receptor gamma (PPARgamma). Consistently, PPARgamma antagonists enhanced, and PPARgamma agonists inhibited MMP9 expression stimulated by ATRA and catalase in THP-1 cells. Therefore, these data indicate that catalase is able to potentiate ATRA-induced macrophage differentiation by inhibition of PPARgamma activity, underscoring an important interplay between H(2)O(2), RA, and PPARgamma in macrophages.

  2. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells

    PubMed Central

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik

    2016-01-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk–/– MSCs. An ex vivo adipogenic differentiation assay showed that Lnk–/– MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R–Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk–/– MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway. PMID:27610032

  3. Peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARβ/δ) gene expression profile on ram spermatozoa and their relation to the sperm motility

    PubMed Central

    Kadivar, Ali; Heidari Khoei, Heidar; Hassanpour, Hossein; Ghanaei, Hamid; Golestanfar, Arefeh; Mehraban, Hossein; Davoodian, Najmeh; Dehghani Tafti, Roohollah

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a member of nuclear receptors superfamily, which mainly regulate the expression of target genes involved in lipid and energy metabolism. These receptors are divided to three isotypes: PPARα, PPARγ and PPARβ/δ. Each isotype has a distinct tissue distribution relating to the distinct functions. In this study, the mRNA abundance for PPARα, PPARγ and PPARβ/δ was evaluated and compared with high and low motile ram spermatozoa. Semen samples from 6 adult rams were fractionated on a two layer discontinuous Percoll gradient to high and low motile sperm and quantitative parameters of sperm motility were determined by CASA. Total RNA was extracted and the mRNA abundance for each gene was measured by relative quantification technique with Real time PCR. The levels of three isotypes of PPAR transcripts were significantly higher in high motile semen samples using quantitative RT-PCR. Some of sperm motility indices were also significantly correlated with PPARα and PPARγ relative expression. This study revealed the novel association of PPAR gene isotypes with sperm motility. Data from our study suggested PPARs are one of the possible factors that can be studied in male infertility. PMID:27226884

  4. Novel Chemical Strategies for Labeling Small Molecule Ligands for Androgen, Progestin, and Peroxisome Proliferator-Activated Receptors for Imaging Prostate and Breast Cancer and the Heart

    SciTech Connect

    Katzenellenbogen, John, A.

    2007-04-19

    Summary of Progress The specific aims of this project can be summarized as follows: • Aim 1: Prepare and evaluate radiolabeled ligands for the peroxisome proliferator-activated receptor (PPAR), a new nuclear hormone receptor target for tumor imaging and hormone therapy. • Aim 2: Prepare steroids labeled with a cyclopentadienyl tricarbonyl technetium or rhenium unit. • Aim 3: Prepare and evaluate other organometallic systems of novel design as ligand mimics and halogenated ligands for nuclear hormone receptor-based tumor imaging. As is described in detail below, we made excellent progress on all three of these aims; the highlights of our progress are the following: • we have prepared the first fluorine-18 labeled analogs of ligands for the PPAR receptor and used these in tissue distribution studies in rats • we have developed three new methods for the synthesis of cyclopentadienyltricarbonyl rhenium and technetium (CpRe(CO)3 and CpTc(CO)3) systems and we have adapted these to the synthesis of steroids labeled with these metals, as well as ligands for other receptor systems • we have prepared a number of fluorine-18 labeled steroidal and non-steroidal androgens and measured their tissue distribution in rats • we have prepared iodine and bromine-labeled progestins with high progesterone receptor binding affinity • we have prepared inorganic metal tricarbonyl complexes and steroid receptor ligands in which the metal tricarbonyl unit is an integral part off the ligand core.

  5. Peroxisome Proliferator-Activated Receptor Activation is Associated with Altered Plasma One-Carbon Metabolites and B-Vitamin Status in Rats.

    PubMed

    Lysne, Vegard; Strand, Elin; Svingen, Gard F T; Bjørndal, Bodil; Pedersen, Eva R; Midttun, Øivind; Olsen, Thomas; Ueland, Per M; Berge, Rolf K; Nygård, Ottar

    2016-01-01

    Plasma concentrations of metabolites along the choline oxidation pathway have been linked to increased risk of major lifestyle diseases, and peroxisome proliferator-activated receptors (PPARs) have been suggested to be involved in the regulation of key enzymes along this pathway. In this study, we investigated the effect of PPAR activation on circulating and urinary one-carbon metabolites as well as markers of B-vitamin status. Male Wistar rats (n = 20) received for 50 weeks either a high-fat control diet or a high-fat diet with tetradecylthioacetic acid (TTA), a modified fatty acid and pan-PPAR agonist with high affinity towards PPARα. Hepatic gene expression of PPARα, PPARβ/δ and the enzymes involved in the choline oxidation pathway were analyzed and concentrations of metabolites were analyzed in plasma and urine. TTA treatment altered most biomarkers, and the largest effect sizes were observed for plasma concentrations of dimethylglycine, nicotinamide, methylnicotinamide, methylmalonic acid and pyridoxal, which were all higher in the TTA group (all p < 0.01). Hepatic Pparα mRNA was increased after TTA treatment, but genes of the choline oxidation pathway were not affected. Long-term TTA treatment was associated with pronounced alterations on the plasma and urinary concentrations of metabolites related to one-carbon metabolism and B-vitamin status in rats. PMID:26742069

  6. Skeletal muscle Heat shock protein 60 increases after endurance training and induces peroxisome proliferator-activated receptor gamma coactivator 1 α1 expression

    PubMed Central

    Barone, Rosario; Macaluso, Filippo; Sangiorgi, Claudia; Campanella, Claudia; Marino Gammazza, Antonella; Moresi, Viviana; Coletti, Dario; Conway de Macario, Everly; Macario, Alberto JL; Cappello, Francesco; Adamo, Sergio; Farina, Felicia; Zummo, Giovanni; Di Felice, Valentina

    2016-01-01

    Heat shock protein 60 (Hsp60) is a chaperone localizing in skeletal muscle mitochondria, whose role is poorly understood. In the present study, the levels of Hsp60 in fibres of the entire posterior group of hindlimb muscles (gastrocnemius, soleus, and plantaris) were evaluated in mice after completing a 6-week endurance training program. The correlation between Hsp60 levels and the expression of four isoforms of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC1α) were investigated only in soleus. Short-term overexpression of hsp60, achieved by in vitro plasmid transfection, was then performed to determine whether this chaperone could have a role in the activation of the expression levels of PGC1α isoforms. The levels of Hsp60 protein were fibre-type specific in the posterior muscles and endurance training increased its content in type I muscle fibers. Concomitantly with the increased levels of Hsp60 released in the blood stream of trained mice, mitochondrial copy number and the expression of three isoforms of PGC1α increased. Overexpressing hsp60 in cultured myoblasts induced only the expression of PGC1 1α, suggesting a correlation between Hsp60 overexpression and PGC1 1 α activation. PMID:26812922

  7. Ginger extract prevents high-fat diet-induced obesity in mice via activation of the peroxisome proliferator-activated receptor δ pathway.

    PubMed

    Misawa, Koichi; Hashizume, Kojiro; Yamamoto, Masaki; Minegishi, Yoshihiko; Hase, Tadashi; Shimotoyodome, Akira

    2015-10-01

    The initiation of obesity entails an imbalance wherein energy intake exceeds expenditure. Obesity is increasing in prevalence and is now a worldwide health problem. Food-derived peroxisome proliferator-activated receptor δ (PPARδ) stimulators represent potential treatment options for obesity. Ginger (Zingiber officinale Roscoe) was previously shown to regulate the PPARγ signaling pathway in adipocytes. In this study, we investigated the antiobesity effects of ginger in vivo and the mechanism of action in vitro. Energy expenditure was increased, and diet-induced obesity was attenuated in C57BL/6J mice treated with dietary ginger extract (GE). GE also increased the number of Type I muscle fibers, improved running endurance capacity and upregulated PPARδ-targeted gene expression in skeletal muscle and the liver. 6-Shogaol and 6-gingerol acted as specific PPARδ ligands and stimulated PPARδ-dependent gene expression in cultured human skeletal muscle myotubes. An analysis of cellular respiration revealed that pretreating cultured skeletal muscle myotubes with GE increased palmitate-induced oxygen consumption rate, which suggested an increase in cellular fatty acid catabolism. These results demonstrated that sustained activation of the PPARδ pathway with GE attenuated diet-induced obesity and improved exercise endurance capacity by increasing skeletal muscle fat catabolism. 6-Shogaol and 6-gingerol may be responsible for the regulatory effects of dietary ginger on PPARδ signaling. PMID:26101135

  8. Expression of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion Is Associated with Peroxisome Proliferator-Activated Receptor Isoform Expression in Term Labor.

    PubMed

    He, Ping; Li, Yuan; Ding, Xiaoying; Sun, Qianqian; Huang, Ying; Gu, Hang; Ni, Xin

    2015-07-01

    Chorionic NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus. Peroxisome proliferator-activated receptors (PPARs) are implicated to be involved in parturition. In this study, we investigated whether PPARs are involved in control of PGDH expression in chorion. The chorionic tissues were collected from the following groups of the women with singleton pregnancy: term no labor (TNL), term labor (TL) and preterm labor (PTL). Chorionic trophoblasts were isolated and cultured in vitro. Immunocytochemistry analysis showed that PPARα, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PGDH, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PPARα, PPARβ, and PPARγ were reduced in TL tissues compared to that of TNL group. PPARα, PPARβ, and PPARγ expression correlated to PGDH in TNL tissues, whereas only PPARγ expression correlated to PGDH in TL chorion tissues. PGDH expression was decreased in PTL tissues compared with TL group, whereas the expression of PPARs was not significantly different between TL and PTL groups. The agonists of three PPARs dose-dependently stimulated PGDH activity, mRNA, and protein expression in cultured chorionic cells. PPARs did not affect the stability of PGDH mRNA but stimulated the transcriptional activity of HPGD gene. Our results suggest that PPARs play pivotal roles in maintenance of PGDH expression in chorion during human pregnancy.

  9. Peroxisome proliferator-activated receptor-{gamma} agonists inhibit the replication of respiratory syncytial virus (RSV) in human lung epithelial cells

    SciTech Connect

    Arnold, Ralf . E-mail: ralf.arnold@medizin.uni-magdeburg.de; Koenig, Wolfgang

    2006-07-05

    We have previously shown that peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) agonists inhibited the inflammatory response of RSV-infected human lung epithelial cells. In this study, we supply evidence that specific PPAR{gamma} agonists (15d-PGJ{sub 2}, ciglitazone, troglitazone, Fmoc-Leu) efficiently blocked the RSV-induced cytotoxicity and development of syncytia in tissue culture (A549, HEp-2). All PPAR{gamma} agonists under study markedly inhibited the cell surface expression of the viral G and F protein on RSV-infected A549 cells. This was paralleled by a reduced cellular amount of N protein-encoding mRNA determined by real-time RT-PCR. Concomitantly, a reduced release of infectious progeny virus into the cell supernatants of human lung epithelial cells (A549, normal human bronchial epithelial cells (NHBE)) was observed. Similar results were obtained regardless whether PPAR{gamma} agonists were added prior to RSV infection or thereafter, suggesting that the agonists inhibited viral gene expression and not the primary adhesion or fusion process.

  10. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-06-03

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration.

  11. Escherichia coli K1 Modulates Peroxisome Proliferator-Activated Receptor γ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis.

    PubMed

    Krishnan, Subramanian; Chang, Alexander C; Stoltz, Brian M; Prasadarao, Nemani V

    2016-10-01

    Escherichia coli K1 meningitis continues to be a major threat to neonatal health. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with endothelial cell glycoprotein 96 (Ecgp96) in the blood-brain barrier to enter the central nervous system. Here we show that the interaction between OmpA and Ecgp96 downregulates peroxisome proliferator-activated receptor γ (PPAR-γ) and glucose transporter 1 (GLUT-1) levels in human brain microvascular endothelial cells, causing disruption of barrier integrity and inhibition of glucose uptake. The suppression of PPAR-γ and GLUT-1 by the bacteria in the brain microvessels of newborn mice causes extensive pathophysiology owing to interleukin 6 production. Pretreatment with partial or selective PPAR-γ agonists ameliorate the pathological outcomes of infection by suppressing interleukin 6 production in the brain. Thus, inhibition of PPAR-γ and GLUT-1 by E. coli K1 is a novel pathogenic mechanism in meningitis, and pharmacological upregulation of PPAR-γ and GLUT-1 levels may provide novel therapeutic avenues. PMID:27456707

  12. Administration of the peroxisomal proliferator-activated receptor {gamma} agonist pioglitazone during fractionated brain irradiation prevents radiation-induced cognitive impairment

    SciTech Connect

    Zhao Weiling; Payne, Valerie; Tommasi, Ellen; Diz, Debra I.; Hsu, F.-C.; Robbins, Mike E. . E-mail: mrobbins@wfubmc.edu

    2007-01-01

    Purpose: We hypothesized that administration of the anti-inflammatory peroxisomal proliferator-activated receptor {gamma} (PPAR{gamma}) agonist pioglitazone (Pio) to adult male rats would inhibit radiation-induced cognitive impairment. Methods and Materials: Young adult male F344 rats received one of the following: (1) fractionated whole brain irradiation (WBI); 40 or 45 Gy {gamma}-rays in 4 or 4.5 weeks, respectively, two fractions per week and normal diet; (2) sham-irradiation and normal diet; (3) WBI plus Pio (120 ppm) before, during, and for 4 or 54 weeks postirradiation; (4) sham-irradiation plus Pio; or (5) WBI plus Pio starting 24h after completion of WBI. Results: Administration of Pio before, during, and for 4 or 54 weeks after WBI prevented Radiation-induced cognitive impairment. Administration of Pio for 54 weeks starting after completion of fractionated WBI substantially but not significantly reduced Radiation-induced cognitive impairment. Conclusions: These findings offer the promise of improving the quality of life and increasing the therapeutic window for brain tumor patients.

  13. The peroxisome proliferators activated receptor-gamma agonists as therapeutics for the treatment of Alzheimer's disease and mild-to-moderate Alzheimer's disease: a meta-analysis.

    PubMed

    Cheng, Huawei; Shang, Yuping; Jiang, Ling; Shi, Tian-lu; Wang, Lin

    2016-01-01

    Alzheimer's disease (AD) is a devastating neurodegenerative disease and there is no effective therapy for it. Peroxisome proliferators activated receptor-gamma (PPAR-γ) agonists is a promising therapeutic approach for AD and has been widely studied recently, but no consensus was available up to now. To clarify this point, a meta-analysis was performed. We searched MEDLINE, EMBASE, Cochrane Central database, PUBMED, Springer Link database, SDOS database, CBM, CNKI and Wan fang database by December 2014. Standardized mean difference (SMD), relative risk (RR) and 95% confidence interval (CI) were calculated to assess the strength of the novel therapeutics for AD and mild-to-moderate AD. A total of nine studies comprising 1314 patients and 1311 controls were included in the final meta-analysis. We found the effect of PPAR-γ agonists on Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-cog) scores by using STATA software. There was no evidence for obvious publication bias in the overall meta-analysis. There is insufficient evidence of statistically incognition of AD and mild-to-moderate AD patients have been improved who were treated with PPAR-γ agonists in our research. However, PPAR-γ agonists may be a promising therapeutic approach in future, especially pioglitazone, with large-scale randomized controlled trials to confirm.

  14. Peroxisome proliferator-activated receptor gamma and retinoid X receptor transcription factors are released from activated human platelets and shed in microparticles.

    PubMed

    Ray, Denise M; Spinelli, Sherry L; Pollock, Stephen J; Murant, Thomas I; O'Brien, Jamie J; Blumberg, Neil; Francis, Charles W; Taubman, Mark B; Phipps, Richard P

    2008-01-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligands are important regulators of lipid metabolism, inflammation, and diabetes. We previously demonstrated that anucleate human platelets express the transcription factor PPARgamma and that PPARgamma ligands blunt platelet activation. To further understand the nature of PPARgamma in platelets, we determined the platelet PPARgamma isoform(s) and investigated the fate of PPARgamma following platelet activation. Our studies demonstrated that human platelets contain only the PPARgamma1 isoform and after activation with thrombin, TRAP, ADP or collagen PPARgamma is released from internal stores. PPARgamma release was blocked by a cytoskeleton inhibitor, Latrunculin A. Platelet-released PPARgamma was complexed with the retinoid X receptor (RXR) and retained its ability to bind DNA. Interestingly, the released PPARgamma and RXR were microparticle associated and the released PPARgamma/RXR complex retained DNA-binding ability. Additionally, a monocytic cell line, THP-1, is capable of internalizing PMPs. Further investigation following treatment of these cells with the PPARgamma agonist, rosiglitazone and PMPs revealed a possible transcellular mechanism to attenuate THP-1 activation. These new findings are the first to demonstrate transcription factor release from platelets, revealing the complex spectrum of proteins expressed and expelled from platelets, and suggests that platelet PPARgamma has an undiscovered role in human biology. PMID:18217139

  15. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells.

    PubMed

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik; Kwon, Sang-Mo

    2016-09-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk (-/-) MSCs. An ex vivo adipogenic differentiation assay showed that Lnk (-/-) MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R-Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk (-/-) MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway. PMID:27610032

  16. Activation of Peroxisome Proliferator-Activated Receptor-γ Reverses Squamous Metaplasia and Induces Transitional Differentiation in Normal Human Urothelial Cells

    PubMed Central

    Varley, Claire Lucy; Stahlschmidt, Jens; Smith, Barbara; Stower, Michael; Southgate, Jennifer

    2004-01-01

    We observed that in urothelium, both cornifying and noncornifying forms of squamous metaplasia are accompanied by changes in the localization of the nuclear hormone receptors, peroxisome proliferator activated receptor γ (PPAR-γ) and retinoid X receptor (RXR-α). To obtain objective evidence for a role for PPAR-γ-mediated signaling in urothelial differentiation, we examined expression of the cytokeratin isotypes CK13, CK20, and CK14 as indicators of transitional, terminal transitional, and squamous differentiation, respectively, in cultures of normal human urothelial cells. In control culture conditions, normal human urothelial cells showed evidence of squamous differentiation (CK14+, CK13−, CK20−). Treatment with the high-affinity PPAR-γ agonist, troglitazone (TZ), resulted in gain of CK13 and loss of CK14 protein expression. The effect of TZ was significantly augmented when the autocrine-stimulated epidermal growth factor receptor pathway was inhibited and this resulted in induction of CK20 expression. The RXR-specific inhibitors PA452, HX531, and HX603 inhibited the TZ-induced CK13 expression, supporting a role for RXR in the induction of CK13 expression. Thus, signaling through PPAR-γ can mediate transitional differentiation of urothelial cells and this is modulated by growth regulatory programs. PMID:15111325

  17. Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.

    PubMed

    Avagyan, Serine; Aguilo, Francesca; Kamezaki, Kenjiro; Snoeck, Hans-Willem

    2011-12-01

    Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

  18. Ginger extract prevents high-fat diet-induced obesity in mice via activation of the peroxisome proliferator-activated receptor δ pathway.

    PubMed

    Misawa, Koichi; Hashizume, Kojiro; Yamamoto, Masaki; Minegishi, Yoshihiko; Hase, Tadashi; Shimotoyodome, Akira

    2015-10-01

    The initiation of obesity entails an imbalance wherein energy intake exceeds expenditure. Obesity is increasing in prevalence and is now a worldwide health problem. Food-derived peroxisome proliferator-activated receptor δ (PPARδ) stimulators represent potential treatment options for obesity. Ginger (Zingiber officinale Roscoe) was previously shown to regulate the PPARγ signaling pathway in adipocytes. In this study, we investigated the antiobesity effects of ginger in vivo and the mechanism of action in vitro. Energy expenditure was increased, and diet-induced obesity was attenuated in C57BL/6J mice treated with dietary ginger extract (GE). GE also increased the number of Type I muscle fibers, improved running endurance capacity and upregulated PPARδ-targeted gene expression in skeletal muscle and the liver. 6-Shogaol and 6-gingerol acted as specific PPARδ ligands and stimulated PPARδ-dependent gene expression in cultured human skeletal muscle myotubes. An analysis of cellular respiration revealed that pretreating cultured skeletal muscle myotubes with GE increased palmitate-induced oxygen consumption rate, which suggested an increase in cellular fatty acid catabolism. These results demonstrated that sustained activation of the PPARδ pathway with GE attenuated diet-induced obesity and improved exercise endurance capacity by increasing skeletal muscle fat catabolism. 6-Shogaol and 6-gingerol may be responsible for the regulatory effects of dietary ginger on PPARδ signaling.

  19. Peroxisome Proliferator-Activated Receptor γ is a Sensitive Target for Oil Sands Process-Affected Water: Effects on Adipogenesis and Identification of Ligands.

    PubMed

    Peng, Hui; Sun, Jianxian; Alharbi, Hattan A; Jones, Paul D; Giesy, John P; Wiseman, Steve

    2016-07-19

    Identification of toxic components of complex mixtures is a challenge. Here, oil sands process-affected water (OSPW) was used as a case study to identify those toxic components with a known protein target. Organic chemicals in OSPW exhibited dose-dependent activation of peroxisome proliferator-activated receptor γ (PPARγ) at concentrations less than those currently in the environment (0.025× equivalent of full-strength OSPW), by use of a luciferase reporter gene assay. Activation of PPARγ-mediated adipogenesis by OSPW was confirmed in 3T3L1 preadipocytes, as evidenced by accumulation of lipids and up-regulation of AP2, LPL, and PPARγ gene expression after exposure to polar fractions of OSPW. Unexpectedly, the nonpolar fractions of OSPW inhibited differentiation of preadipocytes via activation of the Wnt signaling pathway. Organic chemicals in OSPW that were ligands of PPARγ were identified by use of a pull-down system combined with untargeted chemical analysis (PUCA), with a recombinant PPARγ protein. Thirty ligands of PPARγ were identified by use of the PUCA assay. High resolution MS(1) and MS(2) spectra were combined to predict the formulas or structures of a subset of ligands, and polyoxygenated or heteroatomic chemicals, especially hydroxylated carboxylic/sulfonic acids, were the major ligands of PPARγ. PMID:27340905

  20. Constitutive Smad signaling and Smad-dependent collagen gene expression in mouse embryonic fibroblasts lacking peroxisome proliferator-activated receptor-{gamma}

    SciTech Connect

    Ghosh, Asish K Wei, Jun; Wu, Minghua; Varga, John

    2008-09-19

    Transforming growth factor-{beta} (TGF-{beta}), a potent inducer of collagen synthesis, is implicated in pathological fibrosis. Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is a nuclear hormone receptor that regulates adipogenesis and numerous other biological processes. Here, we demonstrate that collagen gene expression was markedly elevated in mouse embryonic fibroblasts (MEFs) lacking PPAR-{gamma} compared to heterozygous control MEFs. Treatment with the PPAR-{gamma} ligand 15d-PGJ{sub 2} failed to down-regulate collagen gene expression in PPAR-{gamma} null MEFs, whereas reconstitution of these cells with ectopic PPAR-{gamma} resulted in their normalization. Compared to control MEFs, PPAR-{gamma} null MEFs displayed elevated levels of the Type I TGF-{beta} receptor (T{beta}RI), and secreted more TGF-{beta}1 into the media. Furthermore, PPAR-{gamma} null MEFs showed constitutive phosphorylation of cellular Smad2 and Smad3, even in the absence of exogenous TGF-{beta}, which was abrogated by the ALK5 inhibitor SB431542. Constitutive Smad2/3 phosphorylation in PPAR-{gamma} null MEFs was associated with Smad3 binding to its cognate DNA recognition sequences, and interaction with coactivator p300 previously implicated in TGF-{beta} responses. Taken together, these results indicate that loss of PPAR-{gamma} in MEFs is associated with upregulation of collagen synthesis, and activation of intracellular Smad signal transduction, due, at least in part, to autocrine TGF-{beta} stimulation.

  1. The Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene Modifies the Association of Physical Activity and Body Mass Changes in Polish Women

    PubMed Central

    Zarebska, Aleksandra; Jastrzebski, Zbigniew; Cieszczyk, Pawel; Leonska-Duniec, Agata; Kotarska, Katarzyna; Kaczmarczyk, Mariusz; Sawczuk, Marek; Maciejewska-Karlowska, Agnieszka

    2014-01-01

    Peroxisome proliferator-activated receptor γ is a key regulator of adipogenesis, responsible for fatty acid storage and maintaining energy balance in the human body. Studies on the functional importance of the PPARG Pro12Ala polymorphic variants indicated that the observed alleles may influence body mass measurements; however, obtained results were inconsistent. We have decided to check if body mass changes observed in physically active participants will be modulated by the PPARG Pro12Ala genotype. The genotype distribution of the PPARG Pro12Ala allele was examined in a group of 201 Polish women measured for selected body mass variables before and after the completion of a 12-week training program. The results of our experiment suggest that PPARG genotype can modulate training-induced body mass measurements changes: after completion of the training program, Pro12/Pro12 homozygotes were characterised by a greater decrease of body fat mass measurements in comparison with 12Ala allele carriers. These results indicate that the PPARG 12Ala variant may impair the training-induced positive effects on body mass measurements; however, the detailed mechanism of such interaction remained unclear and observed correlation between PPARG genotype and body mass differential effects should be interpreted with caution. PMID:25371663

  2. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha increased apoptosis of human endometrial cancer HEC-1A cells

    PubMed Central

    Yang, Hui; Yang, Rui; Liu, Hao; Ren, Zhongqian; Wang, Cuicui; Li, Da; Ma, Xiaoxin

    2016-01-01

    Background Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) coactivates multiple transcription factors and regulates several metabolic processes. In this study, we focused on the roles of PGC-1α in the apoptosis of endometrial cancer HEC-1A cells. Materials and methods PGC-1a expression in the HEC-1A cells was detected with real-time polymerase chain reaction and Western blot. Small interfering RNA directed against PGC-1α was designed and synthesized, and RNA interference technology was used to knock down PGC-1α mRNA and protein expression. Cell apoptosis, cell cycle, and mitochondrial membrane potential were then analyzed using flow cytometry. The expression of apoptotic proteins, Bcl-2 and Bax, was detected with Western blot. Results The specific downregulation of PGC-1α expression in the HEC-1A cells increased their apoptosis through the mitochondrial apoptotic pathway by reducing the expression of Bcl-2 and increasing the expression of Bax. Conclusion These results suggest that PGC-1α influences the apoptosis of HEC-1A cells and also provides a molecular basis for further investigation of the apoptotic mechanism in human endometrial cancer. PMID:27601924

  3. Expression of 15-Hydroxyprostaglandin Dehydrogenase in Human Chorion Is Associated with Peroxisome Proliferator-Activated Receptor Isoform Expression in Term Labor.

    PubMed

    He, Ping; Li, Yuan; Ding, Xiaoying; Sun, Qianqian; Huang, Ying; Gu, Hang; Ni, Xin

    2015-07-01

    Chorionic NAD-dependent 15-hydroxy prostaglandin dehydrogenase (PGDH) plays a pivotal role in controlling the amount of prostaglandins in the uterus. Peroxisome proliferator-activated receptors (PPARs) are implicated to be involved in parturition. In this study, we investigated whether PPARs are involved in control of PGDH expression in chorion. The chorionic tissues were collected from the following groups of the women with singleton pregnancy: term no labor (TNL), term labor (TL) and preterm labor (PTL). Chorionic trophoblasts were isolated and cultured in vitro. Immunocytochemistry analysis showed that PPARα, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PGDH, PPARβ, and PPARγ were localized to trophoblasts in chorion. The protein levels of PPARα, PPARβ, and PPARγ were reduced in TL tissues compared to that of TNL group. PPARα, PPARβ, and PPARγ expression correlated to PGDH in TNL tissues, whereas only PPARγ expression correlated to PGDH in TL chorion tissues. PGDH expression was decreased in PTL tissues compared with TL group, whereas the expression of PPARs was not significantly different between TL and PTL groups. The agonists of three PPARs dose-dependently stimulated PGDH activity, mRNA, and protein expression in cultured chorionic cells. PPARs did not affect the stability of PGDH mRNA but stimulated the transcriptional activity of HPGD gene. Our results suggest that PPARs play pivotal roles in maintenance of PGDH expression in chorion during human pregnancy. PMID:26093984

  4. Peroxisome Proliferator-activated Receptor γ Regulates Genes Involved in Insulin/Insulin-like Growth Factor Signaling and Lipid Metabolism during Adipogenesis through Functionally Distinct Enhancer Classes*

    PubMed Central

    Oger, Frédérik; Dubois-Chevalier, Julie; Gheeraert, Céline; Avner, Stéphane; Durand, Emmanuelle; Froguel, Philippe; Salbert, Gilles; Staels, Bart; Lefebvre, Philippe; Eeckhoute, Jérôme

    2014-01-01

    The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ is a transcription factor whose expression is induced during adipogenesis and that is required for the acquisition and control of mature adipocyte functions. Indeed, PPARγ induces the expression of genes involved in lipid synthesis and storage through enhancers activated during adipocyte differentiation. Here, we show that PPARγ also binds to enhancers already active in preadipocytes as evidenced by an active chromatin state including lower DNA methylation levels despite higher CpG content. These constitutive enhancers are linked to genes involved in the insulin/insulin-like growth factor signaling pathway that are transcriptionally induced during adipogenesis but to a lower extent than lipid metabolism genes, because of stronger basal expression levels in preadipocytes. This is consistent with the sequential involvement of hormonal sensitivity and lipid handling during adipocyte maturation and correlates with the chromatin structure dynamics at constitutive and activated enhancers. Interestingly, constitutive enhancers are evolutionary conserved and can be activated in other tissues, in contrast to enhancers controlling lipid handling genes whose activation is more restricted to adipocytes. Thus, PPARγ utilizes both broadly active and cell type-specific enhancers to modulate the dynamic range of activation of genes involved in the adipogenic process. PMID:24288131

  5. Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population.

    PubMed

    Ke, Tingjing; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Teo, Yik Ying; Goh, Daniel Y T; Tai, E Shyong; Wong, Tien Yin; Cheng, Ching-Yu; Friedlander, Yechiel; Heng, Chew-Kiat

    2016-09-01

    Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) < 0.2) were selected. The effect of interactions between PPAR SNPs and those across the genome on HDL-C was tested using linear regression models. One statistically significant interaction influencing HDL-C was detected between PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, β = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population. PMID:27530449

  6. Nuclear Factor Erythroid 2-Related Factor 2 Drives Podocyte-Specific Expression of Peroxisome Proliferator-Activated Receptor γ Essential for Resistance to Crescentic GN.

    PubMed

    Henique, Carole; Bollee, Guillaume; Lenoir, Olivia; Dhaun, Neeraj; Camus, Marine; Chipont, Anna; Flosseau, Kathleen; Mandet, Chantal; Yamamoto, Masayuki; Karras, Alexandre; Thervet, Eric; Bruneval, Patrick; Nochy, Dominique; Mesnard, Laurent; Tharaux, Pierre-Louis

    2016-01-01

    Necrotizing and crescentic rapidly progressive GN (RPGN) is a life-threatening syndrome characterized by a rapid loss of renal function. Evidence suggests that podocyte expression of the transcription factor peroxisome proliferator-activated receptor γ (PPARγ) may prevent podocyte injury, but the function of glomerular PPARγ in acute, severe inflammatory GN is unknown. Here, we observed marked loss of PPARγ abundance and transcriptional activity in glomerular podocytes in experimental RPGN. Blunted expression of PPARγ in podocyte nuclei was also found in kidneys from patients diagnosed with crescentic GN. Podocyte-specific Pparγ gene targeting accentuated glomerular damage, with increased urinary loss of albumin and severe kidney failure. Furthermore, a PPARγ gain-of-function approach achieved by systemic administration of thiazolidinedione (TZD) failed to prevent severe RPGN in mice with podocyte-specific Pparγ gene deficiency. In nuclear factor erythroid 2-related factor 2 (NRF2)-deficient mice, loss of podocyte PPARγ was observed at baseline. NRF2 deficiency markedly aggravated the course of RPGN, an effect that was partially prevented by TZD administration. Furthermore, delayed administration of TZD, initiated after the onset of RPGN, still alleviated the severity of experimental RPGN. These findings establish a requirement for the NRF2-PPARγ cascade in podocytes, and we suggest that these transcription factors have a role in augmenting the tolerance of glomeruli to severe immune-complex mediated injury. The NRF2-PPARγ pathway may be a therapeutic target for RPGN. PMID:25999406

  7. Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.

    PubMed

    Yao, Pei-Li; Chen, Li Ping; Dobrzański, Tomasz P; Phillips, Dylan A; Zhu, Bokai; Kang, Boo-Hyon; Gonzalez, Frank J; Peters, Jeffrey M

    2015-11-01

    Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARβ/δ in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARβ/δ. Expression of PPARβ/δ caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARβ/δ-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARβ/δ competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARα-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARβ/δ mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARβ/δ inhibits RAR/RXR dimerization and represents a new therapeutic strategy.

  8. Aqueous Extract of Paris polyphylla (AEPP) Inhibits Ovarian Cancer via Suppression of Peroxisome Proliferator-Activated Receptor-Gamma Coactivator (PGC)-1alpha.

    PubMed

    Wang, Chia-Woei; Tai, Cheng-Jeng; Choong, Chen-Yen; Lin, Yu-Chun; Lee, Bao-Hong; Shi, Yeu-Ching; Tai, Chen-Jei

    2016-01-01

    Chemotherapy, a major approach was used in carcinoma treatment, always involves the development of drug resistance as well as side-effects that affect the quality of patients' lives. An association between epithelial-mesenchymal transition (EMT) and chemotherapy resistance was established recently. We demonstrate in this paper that the aqueous extract of Paris polyphylla (AEPP)-a traditional Chinese medicine-can be used in various cancer types for suppression of carcinogenesis. We evaluated the suppressions of EMT and mitochondrial activity by AEPP treatment in a high-glucose (HG) induced-human ovarian carcinoma cell line (OVCAR-3 cells). The mitochondrial morphology was investigated using MitoTracker Deep Red FM staining. Our results indicated that AEPP reduced the viability of OVCAR-3 cells considerably through induction of apoptosis. However, this inhibitory potential of AEPP was attenuated by HG induction in OVCAR-3 cells. The levels of estrogen-related receptor (ERR)-alpha activator and peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1alpha were elevated by HG induction, but were suppressed by AEPP treatment. Down-regulations of cell survival and EMT were oberved in OVCAR-3 cells through suppression of PGC-1alpha by AEPP treatment. These results were confirmed through PGC-1alpha knockdown and overexpression in OVCAR-3 cells. Thus, AEPP can be beneficial for treating ovarian cancer and has potential for development of an integrative cancer therapy against ovarian cancer proliferation, metastasis, and migration. PMID:27271583

  9. LIVER TYPE FATTY ACID BINDING PROTEIN (L-FABP) GENE ABLATION REDUCES NUCLEAR LIGAND DISTRIBUTION AND PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR-α ACTIVITY IN CULTURED PRIMARY HEPATOCYTES1

    PubMed Central

    McIntosh, Avery L.; Atshaves, Barbara P.; Hostetler, Heather A.; Huang, Huan; Davis, Jason; Lyuksyutova, Olga I.; Landrock, Danilo; Kier, Ann B.; Schroeder, Friedhelm

    2009-01-01

    The effect of liver type fatty acid binding protein (L-FABP) gene ablation on the uptake and distribution of long chain fatty acids (LCFA) to the nucleus by real-time laser scanning confocal imaging and peroxisome proliferator activated receptor-α (PPARα) activity was examined in cultured primary hepatocytes from livers wild-type L-FABP+/+ and gene ablated L-FABP−/− mice. Cultured primary hepatocytes from livers of L-FABP−/− mice exhibited: (i) reduced oxidation of palmitic acid, a common dietary long chain fatty acid (LCFA); (ii) reduced expression of fatty acid oxidative enzymes—proteins transcriptionally regulated by PPARα; (iii) reduced palmitic acid-induced PPARα coimmunoprecipitation with coactivator SRC1 concomitant with increased PPARα coimmunoprecipitation with coinhibitor N-CoR; (iv) reduced palmitic acid-induced PPARα. Diminished PPARα activation in L-FABP null hepatocytes was associated with lower uptake of common dietary LCFA (palmitic acid as well as its fluorescent derivative BODIPY FL C16), reduced level of total unesterified LCFA, and real-time redistribution of BODIPY FL C16 from the central nucleoplasm to the nuclear envelope. Taken together, these studies support the hypothesis that L-FABP may facilitate ligand (LCFA)-activated PPARα transcriptional activity at least in part by increasing total LCFA ligand available to PPARα for inducing PPARα-mediated transcription of proteins involved in LCFA metabolism. PMID:19285478

  10. Peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARβ/δ) gene expression profile on ram spermatozoa and their relation to the sperm motility.

    PubMed

    Kadivar, Ali; Heidari Khoei, Heidar; Hassanpour, Hossein; Ghanaei, Hamid; Golestanfar, Arefeh; Mehraban, Hossein; Davoodian, Najmeh; Dehghani Tafti, Roohollah

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a member of nuclear receptors superfamily, which mainly regulate the expression of target genes involved in lipid and energy metabolism. These receptors are divided to three isotypes: PPARα, PPARγ and PPARβ/δ. Each isotype has a distinct tissue distribution relating to the distinct functions. In this study, the mRNA abundance for PPARα, PPARγ and PPARβ/δ was evaluated and compared with high and low motile ram spermatozoa. Semen samples from 6 adult rams were fractionated on a two layer discontinuous Percoll gradient to high and low motile sperm and quantitative parameters of sperm motility were determined by CASA. Total RNA was extracted and the mRNA abundance for each gene was measured by relative quantification technique with Real time PCR. The levels of three isotypes of PPAR transcripts were significantly higher in high motile semen samples using quantitative RT-PCR. Some of sperm motility indices were also significantly correlated with PPARα and PPARγ relative expression. This study revealed the novel association of PPAR gene isotypes with sperm motility. Data from our study suggested PPARs are one of the possible factors that can be studied in male infertility.

  11. Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis.

    PubMed

    David, Valentin; Martin, Aline; Lafage-Proust, Marie-Hélène; Malaval, Luc; Peyroche, Sylvie; Jones, David B; Vico, Laurence; Guignandon, Alain

    2007-05-01

    Because a lack of mechanical information favors the development of adipocytes at the expense of osteoblasts, we hypothesized that the peroxisome proliferator-activated receptor gamma (PPARgamma)-dependent balance between osteoblasts and adipocytes is affected by mechanical stimuli. We tested the robustness of this hypothesis in in vivo rodent osteogenic exercise, in vitro cyclic loading of cancellous haversian bone samples, and cyclic stretching of primary stromal and C3H10T1/2 cells. We found that running rats exhibit a decreased marrow fat volume associated with an increased bone formation, presumably through recruitment of osteoprogenitors. In the tissue culture model and primary stromal cells, cyclic loading induced higher Runx2 and lower PPARgamma2 protein levels. Given the proadipocytic and antiosteoblastic activities of PPARgamma, we studied the effects of cyclic stretching in C3H10T1/2 cells, treated either with the PPARgamma activator, Rosiglitazone, or with GW9662, a potent antagonist of PPARgamma. We found, through both cytochemistry and analysis of lineage marker expression, that under Roziglitazone cyclic stretch partially overcomes the induction of adipogenesis and is still able to favor osteoblast differentiation. Conversely, cyclic stretch has additive effects with GW9662 in inducing osteoblastogenesis. In conclusion, we provide evidence that mechanical stimuli are potential PPARgamma modulators counteracting adipocyte differentiation and inhibition of osteoblastogenesis.

  12. Role of Pleiotropic Properties of Peroxisome Proliferator-Activated Receptors in the Heart: Focus on the Nonmetabolic Effects in Cardiac Protection.

    PubMed

    Barlaka, Eleftheria; Galatou, Eleftheria; Mellidis, Kyriakos; Ravingerova, Tanya; Lazou, Antigone

    2016-02-01

    Peroxisome proliferator-activated receptors, PPARα, PPARβ/δ, and PPARγ, are a group of nuclear receptors that function as transcriptional regulators of lipid metabolism, energy homeostasis, and inflammation. Given the role of metabolism imbalance under pathological states of the heart, PPARs have emerged as important therapeutic targets, and accumulating evidence highlights their protective role in the improvement of cardiac function under diverse pathological settings. Although the role of PPARs in the regulation of cardiac substrate utilization preference and energy homeostasis is well documented, their effects related to the regulation of cellular inflammatory and redox responses in the heart are less studied. In this review, we provide an overview on recent progress with respect to understanding the role of the nonmetabolic effects of PPARs in cardiac dysfunction, namely during ischemia/reperfusion injury, hypertrophy, and cardiac failure, and highlight the mechanisms underlying the protective effects against inflammation, oxidative stress, and cell death. The role of receptor-independent, nongenomic effects of PPAR agonists is also discussed.

  13. Lnk is an important modulator of insulin-like growth factor-1/Akt/peroxisome proliferator-activated receptor-gamma axis during adipogenesis of mesenchymal stem cells

    PubMed Central

    Lee, Jun Hee; Lee, Sang Hun; Lee, Hyang Seon; Ji, Seung Taek; Jung, Seok Yun; Kim, Jae Ho; Bae, Sun Sik

    2016-01-01

    Adipogenic differentiation of mesenchymal stem cells (MSCs) is critical for metabolic homeostasis and nutrient signaling during development. However, limited information is available on the pivotal modulators of adipogenic differentiation of MSCs. Adaptor protein Lnk (Src homology 2B3 [SH2B3]), which belongs to a family of SH2-containing proteins, modulates the bioactivities of different stem cells, including hematopoietic stem cells and endothelial progenitor cells. In this study, we investigated whether an interaction between insulin-like growth factor-1 receptor (IGF-1R) and Lnk regulated IGF-1-induced adipogenic differentiation of MSCs. We found that wild-type MSCs showed greater adipogenic differentiation potential than Lnk–/– MSCs. An ex vivo adipogenic differentiation assay showed that Lnk–/– MSCs had decreased adipogenic differentiation potential compared with wild-type MSCs. Interestingly, we found that Lnk formed a complex with IGF-1R and that IGF-1 induced the dissociation of this complex. In addition, we observed that IGF-1-induced increase in the phosphorylation of Akt and mammalian target of rapamycin was triggered by the dissociation of the IGF-1R–Lnk complex. Expression levels of a pivotal transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ) and its adipogenic target genes (LPL and FABP4) significantly decreased in Lnk–/– MSCs. These results suggested that Lnk adaptor protein regulated the adipogenesis of MSCs through the IGF-1/Akt/PPAR-γ pathway.

  14. Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice.

    PubMed

    Min, Li-Juan; Mogi, Masaki; Shudou, Masachika; Jing, Fei; Tsukuda, Kana; Ohshima, Kousei; Iwanami, Jun; Horiuchi, Masatsugu

    2012-05-01

    We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-γ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-γ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA(y) exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-γ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA(y) mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA(y) mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-γ activation by telmisartan

  15. Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure

    PubMed Central

    Zhang, Li; Ren, Feng; Zhang, Xiangying; Wang, Xinxin; Shi, Hongbo; Zhou, Li; Zheng, Sujun; Chen, Yu; Chen, Dexi; Li, Liying; Duan, Zhongping

    2016-01-01

    ABSTRACT Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF. PMID:27482818

  16. Fatty Acid-binding Proteins 1 and 2 Differentially Modulate the Activation of Peroxisome Proliferator-activated Receptor α in a Ligand-selective Manner*

    PubMed Central

    Hughes, Maria L. R.; Liu, Bonan; Halls, Michelle L.; Wagstaff, Kylie M.; Patil, Rahul; Velkov, Tony; Jans, David A.; Bunnett, Nigel W.; Scanlon, Martin J.; Porter, Christopher J. H.

    2015-01-01

    Nuclear hormone receptors (NHRs) regulate the expression of proteins that control aspects of reproduction, development and metabolism, and are major therapeutic targets. However, NHRs are ubiquitous and participate in multiple physiological processes. Drugs that act at NHRs are therefore commonly restricted by toxicity, often at nontarget organs. For endogenous NHR ligands, intracellular lipid-binding proteins, including the fatty acid-binding proteins (FABPs), can chaperone ligands to the nucleus and promote NHR activation. Drugs also bind FABPs, raising the possibility that FABPs similarly regulate drug activity at the NHRs. Here, we investigate the ability of FABP1 and FABP2 (intracellular lipid-binding proteins that are highly expressed in tissues involved in lipid metabolism, including the liver and intestine) to influence drug-mediated activation of the lipid regulator peroxisome proliferator-activated receptor (PPAR) α. We show by quantitative fluorescence imaging and gene reporter assays that drug binding to FABP1 and FABP2 promotes nuclear localization and PPARα activation in a drug- and FABP-dependent manner. We further show that nuclear accumulation of FABP1 and FABP2 is dependent on the presence of PPARα. Nuclear accumulation of FABP on drug binding is driven largely by reduced nuclear egress rather than an increased rate of nuclear entry. Importin binding assays indicate that nuclear access occurs via an importin-independent mechanism. Together, the data suggest that specific drug-FABP complexes can interact with PPARα to effect nuclear accumulation of FABP and NHR activation. Because FABPs are expressed in a regionally selective manner, this may provide a means to tailor the patterns of NHR drug activation in a tissue-specific manner. PMID:25847235

  17. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population

    PubMed Central

    Rooki, Hassan; Haerian, Monir-Sadat; Azimzadeh, Pedram; Ebrahimi, Mahmoud; Mirhafez, Reza; Ferns, Gordon; Ghayour-Mobarhan, Majid; Zali, Mohammad-Reza

    2013-01-01

    BACKGROUND: Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. MATERIALS AND METHODS: Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. RESULTS: The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. CONCLUSIONS: Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences. PMID:24497707

  18. The Differential Interactions of Peroxisome Proliferator-Activated Receptor [gamma] Ligands with Tyr473 Is a Physical Basis for Their Unique Biological Activities

    SciTech Connect

    Einstein, Monica; Akiyama, Taro E.; Castriota, Gino A.; Wang, Chuanlin F.; McKeever, Brian; Mosley, Ralph T.; Becker, Joseph W.; Moller, David E.; Meinke, Peter T.; Wood, Harold B.; Berger, Joel P.

    2008-08-01

    Despite their proven antidiabetic efficacy, widespread use of peroxisome proliferator-activated receptor (PPAR){gamma} agonists has been limited by adverse cardiovascular effects. To overcome this shortcoming, selective PPAR{gamma} modulators (SPPAR{gamma}Ms) have been identified that have antidiabetic efficacy comparable with full agonists with improved tolerability in preclinical species. The results of structural studies support the proposition that SPPAR{gamma}Ms interact with PPAR{gamma} differently from full agonists, thereby providing a physical basis for their novel activities. Herein, we describe a novel PPAR{gamma} ligand, SPPAR{gamma}M2. This compound was a partial agonist in a cell-based transcriptional activity assay, with diminished adipogenic activity and an attenuated gene signature in cultured human adipocytes. X-ray cocrystallography studies demonstrated that, unlike rosiglitazone, SPPAR{gamma}M2 did not interact with the Tyr473 residue located within helix 12 of the ligand binding domain (LBD). Instead, SPPAR{gamma}M2 was found to bind to and activate human PPAR{gamma} in which the Tyr473 residue had been mutated to alanine (hPPAR{gamma}Y473A), with potencies similar to those observed with the wild-type receptor (hPPAR{gamma}WT). In additional studies, we found that the intrinsic binding and functional potencies of structurally distinct SPPAR{gamma}Ms were not diminished by the Y473A mutation, whereas those of various thiazolidinedione (TZD) and non-TZD PPAR{gamma} full agonists were reduced in a correlative manner. These results directly demonstrate the important role of Tyr473 in mediating the interaction of full agonists but not SPPAR{gamma}Ms with the PPAR{gamma} LBD, thereby providing a precise molecular determinant for their differing pharmacologies.

  19. Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms and gene-gene interaction with asthma risk in a Chinese adults population

    PubMed Central

    Li, Wancheng; Dai, Wenjing; Sun, Jian; Zhang, Wei; Jiang, Yi; Ma, Chunlan; Wang, Chunmao; He, Jie

    2015-01-01

    Aims: To investigate the association between single nucleotide polymorphism (SNP) of peroxisome proliferator-activated receptors γ (PPAR γ) and additional gene-gene interactions on asthma risk. Methods: A total of 882 subjects (602 males, 280 females), with a mean age of 61.3±14.8 years old, including 430 asthma patients and 452 normal subjects were selected in this study, including the genotyping of polymorphisms. Logistic regression was performed to investigate association between SNP and asthma. Generalized MDR (GMDR) was used to analysis the interaction among four SNP. Results: Asthma risk was significantly lower in carriers of Ala allele of the rs1805192 polymorphism than those with Pro/Pro (Pro/Ala+ Ala/Ala versus Pro/Pro, adjusted OR (95% CI)=0.70 (0.51-0.94). In addition, we also found a significant association between rs10865710 and asthma, asthma risk was significantly lower in carriers of G allele of the rs10865710 polymorphism than those with CC (CG+ GG versus CC, adjusted OR (95% CI)=0.68 (0.55-0.95). There was a significant three-locus model (P=0.0107) involving rs1805192, rs10865710 and rs709158, indicating a potential gene-gene interaction among rs1805192, rs10865710 and rs709158. Overall, the three-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72% after covariates adjustment. Conclusions: Our results support an important association of rs1805192 and rs10865710 with asthma, and additional interaction among rs1805192, rs10865710 and rs709158. PMID:26770574

  20. Peroxisome proliferator-activated receptor gamma (PPARγ) in yellow catfish Pelteobagrus fulvidraco: molecular characterization, mRNA expression and transcriptional regulation by insulin in vivo and in vitro.

    PubMed

    Zheng, Jia-Lang; Zhuo, Mei-Qin; Luo, Zhi; Pan, Ya-Xiong; Song, Yu-Feng; Huang, Chao; Zhu, Qing-Ling; Hu, Wei; Chen, Qi-Liang

    2015-02-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is ligand-inducible transcription factor and has important roles in lipid metabolism, cell proliferation and inflammation. In the present study, yellow catfish Pelteobagrus fulvidraco PPARγ cDNA was isolated from liver by RT-PCR and RACE, and its molecular characterization and transcriptional regulation by insulin in vivo and in vitro were determined. The generation of PPARγ1 and PPARγ2 was due to alternative promoter of PPARγ gene. PPARγ1 and PPARγ2 mRNA covered 2426 bp and 2537 bp, respectively, with an open reading frame (ORF) of 1584 bp encoding 527 amino acid residues. Yellow catfish PPARγ gene was organized in a manner similar to that of their mammalian homologs, implying a modular organization of the protein's domains. A comparison between the yellow catfish PPARγ amino acid sequence and the correspondent sequences of several other species revealed the identity of 55-76.2%. Two PPARγ transcripts (PPARγ1 and PPARγ2) mRNAs were expressed in a wide range of tissues, but the abundance of each PPARγ mRNA showed the tissue- and developmental stage-dependent expression patterns. Intraperitoneal injection of insulin in vivo significantly stimulated the mRNA expression of total PPARγ and PPARγ1, but not PPARγ2 in the liver of yellow catfish. In contrast, incubation of hepatocytes with insulin in vitro increased the mRNA levels of PPARγ1, PPARγ2 and total PPARγ. To our knowledge, for the first time, the present study provides evidence that PPARγ1 and PPARγ2 are differentially expressed with and among tissues during different developmental stages and also regulated by insulin both in vivo and in vitro, which serves to increase our understanding on PPARγ physiological function in fish. PMID:25637673

  1. Peroxisome proliferator-activated receptorβ/δ activation is essential for modulating p-Foxo1/Foxo1 status in functional insulin-positive cell differentiation.

    PubMed

    Li, L; Li, T; Zhang, Y; Pan, Z; Wu, B; Huang, X; Zhang, Y; Mei, Y; Ge, L; Shen, G; Ge, R-s; Zhu, D; Lou, Y

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) participate in energy homeostasis and play essential roles in diabetes therapy through their effects on non-pancreas tissues. Pathological microenvironment may influence the metabolic requirements for the maintenance of stem cell differentiation. Accordingly, understanding the mechanisms of PPARs on pancreatic β-cell differentiation may be helpful to find the underlying targets of disrupted energy homeostasis under the pancreatic disease condition. PPARs are involved in stem cell differentiation via mitochondrial oxidative phosphorylation, but the subtype member activation and the downstream regulation in functional insulin-positive (INS+) cell differentiation remain unclear. Here, we show a novel role of PPARβ/δ activation in determining INS+ cell differentiation and functional maturation. We found PPARβ/δ expression selectively upregulated in mouse embryonic pancreases or stem cells-derived INS+ cells at the pancreatic mature stage in vivo and in vitro. Strikingly, given the inefficiency of generating INS+ cells in vitro, PPARβ/δ activation displayed increasing mouse and human ES cell-derived INS+ cell numbers and insulin secretion. This phenomenon was closely associated with the forkhead box protein O1 (Foxo1) nuclear shuttling, which was dependent on PPARβ/δ downstream PI3K/Akt signaling transduction. The present study reveals the essential role of PPARβ/δ activation on p-Foxo1/Foxo1 status, and in turn, determining INS+ cell generation and insulin secretion via affecting pancreatic and duodenal homeobox-1 expression. The results demonstrate the underlying mechanism by which PPARβ/δ activation promotes functional INS+ cell differentiation. It also provides potential targets for anti-diabetes drug discovery and hopeful clinical applications in human cell therapy. PMID:25855963

  2. Inhibitors of Growth 1b Suppresses Peroxisome Proliferator-Activated Receptor-β/δ Expression Through Downregulation of Hypoxia-Inducible Factor 1α in Osteoblast Differentiation.

    PubMed

    Qu, Bo; Hong, Zhen; Gong, Kai; Sheng, Jun; Wu, Hong-Hua; Deng, Shao-Lin; Huang, Gang; Ma, Ze-Hui; Pan, Xian-Ming

    2016-04-01

    Bone formation, a highly regulated developmental process, involves osteoblast differentiation, which is controlled by different important transcription factors. Recent evidence has suggested possible negative regulation of inhibitors of growth (ING) 1b on the osteoblast marker expression. The aim of this study is to examine the detailed mechanism by which the activity of ING1b inhibits osteoblast differentiation. In the current study, we investigated the function and mechanism by which ING1b inhibits osteoblast differentiation using C3H10T1/2 mesenchymal stem cells and MC3T3-E1 preosteoblasts. Real-time polymerase chain reaction and Western blotting showed that ING1b was decreased during osteoblast differentiation and ING1b overexpression markedly decreased alkaline phosphatase (ALP) activity, runt-related transcription factor 2 (Runx2) expression, and collagen type 1 synthesis, whereas ING1b silencing significantly upregulated ALP activity, Runx2 expression, and collagen type 1 synthesis. Further studies indicated that ING1b suppressed the expression of peroxisome proliferator-activated receptor (PPAR)-β/δ in a hypoxia-inducible factor (HIF) 1α-dependent manner, while ING1b silencing significantly increased the expression of PPAR-β/δ and HIF1α. Moreover, PPAR-β/δ or HIF1α silencing significantly inhibited ALP activity, Runx2 expression, and collagen type 1 synthesis. These results demonstrated that ING1b is an important regulator of osteoblast differentiation and suppresses PPAR-β/δ. Our study may provide additional insight into osteoblast differentiation and offer a potential new molecular target for osteoporosis. PMID:26849833

  3. Enhanced pan-peroxisome proliferator-activated receptor gene and protein expression in adipose tissue of diet-induced obese mice treated with telmisartan.

    PubMed

    Penna-de-Carvalho, Aline; Graus-Nunes, Francielle; Rabelo-Andrade, Júlia; Mandarim-de-Lacerda, Carlos Alberto; Souza-Mello, Vanessa

    2014-12-01

    Telmisartan has previously been used to target obesity, showing peroxisome proliferator-activated receptor (PPAR) β/δ-related effects in white adipose tissue (WAT). We sought to evaluate whether telmisartan enhances gene and protein expression of all PPAR isoforms in WAT and brown adipose tissue (BAT), as well as their downstream effects upon insulin resistance, adipokine profile and adaptive thermogenesis. Male C57BL/6 mice were fed standard chow (SC; 10% lipids) or high-fat diet (HF; 50% lipids) for 10 weeks. Animals were then randomly allocated into the following four groups: SC, SC-T, HF and HF-T. Telmisartan [10 mg (kg diet)(-1)] was administered for 4 weeks in the diet. Animals in the HF group were overweight and exhibited hypertension, insulin resistance, decreased energy expenditure, a pro-inflammatory adipokine profile and abnormal fat pad mass distribution. Animals in the HF group showed decreased expression of PPARα, β/δ and γ in WAT and BAT, resulting in impaired glucose uptake and insufficient thermogenesis. Due to the improvement in the adipokine profile and enhanced insulin sensitivity with adequate insulin-stimulated glucose uptake after treatment with telmisartan, the activation of all PPAR isoforms in WAT was beneficial. In BAT, telmisartan induced sustained sympathetic activation, because the β3-adrenergic receptor was induced by PPARβ/δ, while uncoupling protein 1 was induced by PPARα to promote thermogenesis. Telmisartan exerted anti-obesity effects through higher pan-PPAR gene and protein expression. Upon PPARα, β/δ and γ (pan-PPAR) agonism in adipose tissue of obese mice, telmisartan ameliorates inflammation and insulin resistance, as well as inducing non-shivering thermogenesis. Our results point to new therapeutic targets for the control of obesity and comorbidities through pan-PPAR-related effects. PMID:25326526

  4. Telomerase Reverse Transcriptase and Peroxisome Proliferator-Activated Receptor γ Co-Activator-1α Cooperate to Protect Cells from DNA Damage and Mitochondrial Dysfunction in Vascular Senescence.

    PubMed

    Mendelsohn, Andrew R; Larrick, James W

    2015-10-01

    Reduced telomere length with increasing age in dividing cells has been implicated in contributing to the pathologies of human aging, which include cardiovascular and metabolic disorders, through induction of cellular senescence. Telomere shortening results from the absence of telomerase, an enzyme required to maintain telomere length. Telomerase reverse transcriptase (TERT), the protein subunit of telomerase, is expressed only transiently in a subset of adult somatic cells, which include stem cells and smooth muscle cells. A recent report from Xiong and colleagues demonstrates a pivotal role for the transcription co-factor peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) in maintaining TERT expression and preventing vascular senescence and atherosclerosis in mice. Ablation of PGC-1α reduced TERT expression and increased DNA damage and reactive oxygen species (ROS), resulting in shortened telomeres and vascular senescence. In the ApoE(-/-) mouse model of atherosclerosis, forced expression of PGC-1α increased expression of TERT, extended telomeres, and reversed genomic DNA damage, vascular senescence, and the development of atherosclerotic plaques. Alpha lipoic acid (ALA) stimulated expression of PGC-1α and TERT and reversed DNA damage, vascular senescence, and atherosclerosis, similarly to ectopic expression of PGC-1α. ALA stimulated cyclic adenosine monophosphate (cAMP) signaling, which in turn activated the cAMP response element-binding protein (CREB), a co-factor for PGC-1α expression. The possibility that ALA might induce TERT to extend telomeres in human cells suggests that ALA may be useful in treating atherosclerosis and other aging-related diseases. However, further investigation is needed to identify whether ALA induces TERT in human cells, which cell types are susceptible, and whether such changes have clinical significance. PMID:26414604

  5. Toll-like receptor 4 mediates cross-talk between peroxisome proliferator-activated receptor γ and nuclear factor-κB in macrophages

    PubMed Central

    Necela, Brian M; Su, Weidong; Thompson, E Aubrey

    2008-01-01

    The peroxisome proliferator-activated receptor γ (PPARγ) is expressed in macrophages and plays an important role in suppressing the inflammatory response. Lipopolysaccharides (LPS), which activate Toll-like receptor 4 (TLR4), reduced PPARγ expression and function in peritoneal macrophages and macrophage cell lines. Moreover, pretreatment with the synthetic PPARγ ligand, rosiglitazone did not prevent LPS-mediated downregulation of PPARγ. Inhibition of PPARγ expression was not blocked by cycloheximide, indicating that de novo protein synthesis is not required for LPS-mediated suppression of PPARγ. Destabilization of PPARγ messenger RNA (mRNA) was not observed in LPS-stimulated macrophages, suggesting that LPS regulates the synthesis of PPARγ mRNA. LPS had no effect on PPARγ expression in macrophages from TLR4 knockout mice, whereas LPS inhibited PPARγ expression in cells that had been reconstituted to express functional TLR4. Targeting the TLR4 pathway with inhibitors of MEK1/2, p38, JNK and AP-1 had no effect on PPARγ downregulation by LPS. However, inhibitors that target NEMO, IκB and NF-κB abolished LPS-mediated downregulation of PPARγ in LPS-stimulated macrophages. Our data indicate that activation of TLR4 inhibits PPARγ mRNA synthesis by an NF-κB-dependent mechanism. Low-density genomic profiling of macrophage-specific PPARγ knockout cells indicated that PPARγ suppresses inflammation under basal conditions, and that loss of PPARγ expression is sufficient to induce a proinflammatory state. Our data reveal a regulatory feedback loop in which PPARγ represses NF-κB-mediated inflammatory signalling in unstimulated macrophages; however, upon activation of TLR4, NF-κB drives down PPARγ expression and thereby obviates any potential anti-inflammatory effects of PPARγ in LPS-stimulated macrophages. PMID:18422969

  6. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145

    SciTech Connect

    Zhu, Hua-Yu; Li, Chao; Zheng, Zhao; Zhou, Qin; Guan, Hao; Su, Lin-Lin; Han, Jun-Tao; Zhu, Xiong-Xiang; Wang, Shu-yue; Li, Jun Hu, Da-Hai

    2015-03-27

    The transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) functions to regulate cell differentiation and lipid metabolism. Recently, its agonist has been documented to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanisms and gene interactions in hypertrophic scar fibroblasts (HSFBs) in vitro. HSFBs were cultured and treated with or without PPAR-γ agonist or antagonist for gene expression. Bioinformatical analysis predicted that miR-145 could target Smad3 expression. Luciferase assay was used to confirm such an interaction. The data showed that PPAR-γ agonist troglitazone suppressed expression of Smad3 and Col1 in HSFBs. PPAR-γ agonist induced miR-145 at the gene transcriptional level, which in turn inhibited Smad3 expression and Col1 level in HSFBs. Furthermore, ELISA data showed that Col1 level in HSFBs was controlled by a feedback regulation mechanism involved in PPAR-γ agonist and antagonist-regulated expression of miR-145 and Smad3 in HSFBs. These findings indicate that PPAR-γ-miR-145-Smad3 axis plays a role in regulation of collagen synthesis in HSFBs. - Highlights: • PPAR-γ agonist inhibits collagen synthesis in HSFBs. • Smad3 and type I collagen expression are decreased by PPAR-γ agonist. • miR-145 expression is increased by PPAR-γ agonist in HSFBs. • Increased miR-145 inhibits collagen synthesis by targeting Smad3. • miR-145 regulates collagen synthesis.

  7. Gene expression profiling of potential peroxisome proliferator-activated receptor (PPAR) target genes in human hepatoblastoma cell lines inducibly expressing different PPAR isoforms

    PubMed Central

    Tachibana, Keisuke; Kobayashi, Yumi; Tanaka, Toshiya; Tagami, Masayuki; Sugiyama, Akira; Katayama, Tatsuya; Ueda, Chihiro; Yamasaki, Daisuke; Ishimoto, Kenji; Sumitomo, Mikako; Uchiyama, Yasutoshi; Kohro, Takahide; Sakai, Juro; Hamakubo, Takao; Kodama, Tatsuhiko; Doi, Takefumi

    2005-01-01

    Background Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and commonly play an important role in the regulation of lipid homeostasis. To identify human PPARs-responsive genes, we established tetracycline-regulated human hepatoblastoma cell lines that can be induced to express each human PPAR and investigated the gene expression profiles of these cells. Results The expression of each introduced PPAR gene was investigated using the various concentrations of doxycycline in the culture media. We found that the expression of each PPAR subtype was tightly controlled by the concentration of doxycycline in these established cell lines. DNA microarray analyses using these cell lines were performed with or without adding each subtype ligand and provided much important information on the PPAR target genes involved in lipid metabolism, transport, storage and other activities. Interestingly, it was noted that while ligand-activated PPARδ induced target gene expression, unliganded PPARδ repressed these genes. The real-time RT-PCR was used to verify the altered expression of selected genes by PPARs and we found that these genes were induced to express in the same pattern as detected in the microarray analyses. Furthermore, we analysed the 5'-flanking region of the human adipose differentiation-related protein (adrp) gene that responded to all subtypes of PPARs. From the detailed analyses by reporter assays, the EMSAs, and ChIP assays, we determined the functional PPRE of the human adrp gene. Conclusion The results suggest that these cell lines are important tools used to identify the human PPARs-responsive genes. PMID:16197558

  8. Phosphorylation of extracellular signal-regulated kinase (ERK)-1/2 Is associated with the downregulation of peroxisome proliferator-activated receptor (PPAR)-γ during polymicrobial sepsis.

    PubMed

    Kaplan, Jennifer M; Hake, Paul W; Denenberg, Alvin; Nowell, Marchele; Piraino, Giovanna; Zingarelli, Basilia

    2010-01-01

    Peroxisome proliferator-activated receptor (PPAR)-γ is a ligand-activated transcription factor and regulates inflammation. Posttranslational modifications regulate the function of PPARγ, potentially affecting inflammation. PPARγ contains a mitogen-activated protein kinase (MAPK) site, and phosphorylation by extracellular signal-regulated kinase (ERK)-1/2 leads to inhibition of PPARγ. This study investigated the kinetics of PPARγ expression and activation in parenchymal and immune cells in sepsis using the MAPK/ERK kinase (MEK)-1 inhibitor, an upstream kinase of ERK1/2. Adult male Sprague Dawley rats were subjected to polymicrobial sepsis by cecal ligation and puncture. Rats received intraperitoneal injection of vehicle or the MEK1 inhibitor PD98059 (5 mg/kg) 30 min before cecal ligation and puncture. Rats were euthanized at 0, 1, 3, 6 and 18 h after cecal ligation and puncture. Control animals used were animals at time 0 h. Lung, plasma and peripheral blood mononuclear cells (PBMCs) were collected for biochemical assays. In vehicle-treated rats, polymicrobial sepsis resulted in significant lung injury. In the lung and PBMCs, nuclear levels of PPARγ were decreased and associated with an increase in phosphorylated PPARγ and phosphorylated ERK1/2 levels. Treatment with the MEK1 inhibitor increased the antiinflammatory plasma adipokine adiponectin, restored PPARγ expression in PBMCs and lung, and decreased lung injury. The inflammatory effects of sepsis cause changes in PPARγ expression and activation, in part, because of phosphorylation of PPARγ by ERK1/2. This phosphorylation can be reversed by ERK1/2 inhibition, thereby improving lung injury.

  9. Peroxisome proliferator-activated receptor γ controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus.

    PubMed

    Garretson, John T; Teubner, Brett J W; Grove, Kevin L; Vazdarjanova, Almira; Ryu, Vitaly; Bartness, Timothy J

    2015-03-18

    Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors.

  10. Body Mass Index in Pregnancy Does Not Affect Peroxisome Proliferator-activated Receptor Gamma Promoter Region (−359 to −260) Methylation in the Neonate

    PubMed Central

    Casamadrid, VRE; Amaya, CA; Mendieta, ZH

    2016-01-01

    Background: Obesity in pregnancy can contribute to epigenetic changes. Aim: To assess whether body mass index (BMI) in pregnancy is associated with changes in the methylation of the peroxisome proliferator-activated receptor γ (PPAR) promoter region (-359 to - 260) in maternal and neonatal leukocytes. Subjects and Methods: In this matched, cohort study 41 pregnant women were allocated into two groups: (a) Normal weight (n = 21) and (b) overweight (n = 20). DNA was extracted from maternal and neonatal leukocytes (4000-10,000 cells) in MagNA Pure (Roche) using MagNA Pure LC DNA Isolation Kit 1 (Roche, Germany). Treatment of DNA (2 μg) was performed with sodium bisulfite (EZ DNA Methylation-Direct™ Kit; Zymo Research). Real-time quantitative polymerase chain reaction (qPCR) was performed in a LightCycler 2.0 (Roche) using the SYBR® Advantage® qPCR Premix Kit (Clontech). The primers used for PPARγ coactivator (PPARG) M3 were 5’- aagacggtttggtcgatc-3’ (forward), and5’- cgaaaaaaaatccgaaatttaa-3’ (reverse) and those for PPARG unmethylated were: 5’-gggaagatggtttggttgatt-3’ (forward) and 5’- ttccaaaaaaaaatccaaaatttaa-3’ (reverse). Intergroup differences were calculated using the Mann-Whitney U-test, and intragroup differences, with the Wilcoxon test (IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp.). Results: Significant differences were found in BMI, pregestational weight, and postdelivery weight between groups but not in the methylation status of the PPARγ promoter region (-359 to - 260). Conclusion: The PPARγ promoter region (-359 to - 260) in peripheral leukocytes is unlikely to get an obesity-induced methylation in pregnancy. PMID:27144075

  11. Peroxisome proliferator-activated receptor alpha acts as a mediator of endoplasmic reticulum stress-induced hepatocyte apoptosis in acute liver failure.

    PubMed

    Zhang, Li; Ren, Feng; Zhang, Xiangying; Wang, Xinxin; Shi, Hongbo; Zhou, Li; Zheng, Sujun; Chen, Yu; Chen, Dexi; Li, Liying; Zhao, Caiyan; Duan, Zhongping

    2016-07-01

    Peroxisome proliferator-activated receptor α (PPARα) is a key regulator to ameliorate liver injury in cases of acute liver failure (ALF). However, its regulatory mechanisms remain largely undetermined. Endoplasmic reticulum stress (ER stress) plays an important role in a number of liver diseases. This study aimed to investigate whether PPARα activation inhibits ER stress-induced hepatocyte apoptosis, thereby protecting against ALF. In a murine model of D-galactosamine (D-GalN)- and lipopolysaccharide (LPS)-induced ALF, Wy-14643 was administered to activate PPARα, and 4-phenylbutyric acid (4-PBA) was administered to attenuate ER stress. PPARα activation ameliorated liver injury, because pre-administration of its specific inducer, Wy-14643, reduced the serum aminotransferase levels and preserved liver architecture compared with that of controls. The protective effect of PPARα activation resulted from the suppression of ER stress-induced hepatocyte apoptosis. Indeed, (1) PPARα activation decreased the expression of glucose-regulated protein 78 (Grp78), Grp94 and C/EBP-homologous protein (CHOP) in vivo; (2) the liver protection by 4-PBA resulted from the induction of PPARα expression, as 4-PBA pre-treatment promoted upregulation of PPARα, and inhibition of PPARα by small interfering RNA (siRNA) treatment reversed liver protection and increased hepatocyte apoptosis; (3) in vitro PPARα activation by Wy-14643 decreased hepatocyte apoptosis induced by severe ER stress, and PPARα inhibition by siRNA treatment decreased the hepatocyte survival induced by mild ER stress. Here, we demonstrate that PPARα activation contributes to liver protection and decreases hepatocyte apoptosis in ALF, particularly through regulating ER stress. Therefore, targeting PPARα could be a potential therapeutic strategy to ameliorate ALF. PMID:27482818

  12. Dietary α-Eleostearic Acid Ameliorates Experimental Inflammatory Bowel Disease in Mice by Activating Peroxisome Proliferator-Activated Receptor-γ

    PubMed Central

    Lewis, Stephanie N.; Brannan, Lera; Guri, Amir J.; Lu, Pinyi; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2011-01-01

    Background Treatments for inflammatory bowel disease (IBD) are modestly effective and associated with side effects from prolonged use. As there is no known cure for IBD, alternative therapeutic options are needed. Peroxisome proliferator-activated receptor-gamma (PPARγ) has been identified as a potential target for novel therapeutics against IBD. For this project, compounds were screened to identify naturally occurring PPARγ agonists as a means to identify novel anti-inflammatory therapeutics for experimental assessment of efficacy. Methodology/Principal Findings Here we provide complementary computational and experimental methods to efficiently screen for PPARγ agonists and demonstrate amelioration of experimental IBD in mice, respectively. Computational docking as part of virtual screening (VS) was used to test binding between a total of eighty-one compounds and PPARγ. The test compounds included known agonists, known inactive compounds, derivatives and stereoisomers of known agonists with unknown activity, and conjugated trienes. The compound identified through VS as possessing the most favorable docked pose was used as the test compound for experimental work. With our combined methods, we have identified α-eleostearic acid (ESA) as a natural PPARγ agonist. Results of ligand-binding assays complemented the screening prediction. In addition, ESA decreased macrophage infiltration and significantly impeded the progression of IBD-related phenotypes through both PPARγ-dependent and –independent mechanisms in mice with experimental IBD. Conclusions/Significance This study serves as the first significant step toward a large-scale VS protocol for natural PPARγ agonist screening that includes a massively diverse ligand library and structures that represent multiple known target pharmacophores. PMID:21904603

  13. Peroxisome proliferator-activated receptor γ controls ingestive behavior, agouti-related protein, and neuropeptide Y mRNA in the arcuate hypothalamus.

    PubMed

    Garretson, John T; Teubner, Brett J W; Grove, Kevin L; Vazdarjanova, Almira; Ryu, Vitaly; Bartness, Timothy J

    2015-03-18

    Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. PMID:25788674

  14. Protective Role for Tissue Inhibitor of Metalloproteinase-4, a Novel Peroxisome Proliferator-Activated Receptor-γ Target Gene, in Smooth Muscle in Deoxycorticosterone Acetate-Salt Hypertension.

    PubMed

    Ketsawatsomkron, Pimonrat; Keen, Henry L; Davis, Deborah R; Lu, Ko-Ting; Stump, Madeliene; De Silva, T Michael; Hilzendeger, Aline M; Grobe, Justin L; Faraci, Frank M; Sigmund, Curt D

    2016-01-01

    Loss of peroxisome proliferator-activated receptor-γ (PPARγ) function causes hypertension, whereas its activation lowers blood pressure. Evidence suggests that these effects may be attributable to PPARγ activity in the vasculature. However, the specific transcriptional targets of PPARγ in vessels remain largely unidentified. In this study, we examined the role of smooth muscle PPARγ during salt-sensitive hypertension and investigated its transcriptional targets and functional effect. Transgenic mice expressing dominant-negative PPARγ (S-P467L) in smooth muscle cells were more prone to deoxycorticosterone acetate-salt-induced hypertension and mesenteric arterial dysfunction compared with nontransgenic controls. Despite similar morphometry at baseline, vascular remodeling in conduit and small arteries was enhanced in S-P467L after deoxycorticosterone acetate-salt treatment. Gene expression profiling in aorta and mesenteric arteries revealed significantly decreased expression of tissue inhibitor of metalloproteinase-4 (TIMP-4) in S-P467L. Expression of TIMP-4 was increased by deoxycorticosterone acetate-salt treatment, but this increase was ablated in S-P467L. Interference with PPARγ activity either by treatment with a PPARγ inhibitor, GW9662, or by expressing P467L PPARγ markedly suppressed TIMP-4 in primary smooth muscle cells. PPARγ binds to a PPAR response element (PPRE) in chromatin close to the TIMP-4 gene in smooth muscle cells, suggesting that TIMP-4 is a novel target of PPARγ. The interference with PPARγ and decrease in TIMP-4 were accompanied by an increase in total matrix metalloproteinase activity. PPARγ-mediated loss of TIMP-4 increased, whereas overexpression of TIMP-4 decreased smooth muscle cell migration in a scratch assay. Our findings highlight a protective mechanism induced by PPARγ in deoxycorticosterone acetate-salt treatment, establishing a novel mechanistic link between PPARγ and TIMP-4.

  15. Distinct properties of telmisartan on agonistic activities for peroxisome proliferator-activated receptor γ among clinically used angiotensin II receptor blockers: drug-target interaction analyses.

    PubMed

    Kakuta, Hirotoshi; Kurosaki, Eiji; Niimi, Tatsuya; Gato, Katsuhiko; Kawasaki, Yuko; Suwa, Akira; Honbou, Kazuya; Yamaguchi, Tomohiko; Okumura, Hiroyuki; Sanagi, Masanao; Tomura, Yuichi; Orita, Masaya; Yonemoto, Takako; Masuzaki, Hiroaki

    2014-04-01

    A proportion of angiotensin II type 1 receptor blockers (ARBs) improves glucose dyshomeostasis and insulin resistance in a clinical setting. Of these ARBs, telmisartan has the unique property of being a partial agonist for peroxisome proliferator-activated receptor γ (PPARγ). However, the detailed mechanism of how telmisartan acts on PPARγ and exerts its insulin-sensitizing effect is poorly understood. In this context, we investigated the agonistic activity of a variety of clinically available ARBs on PPARγ using isothermal titration calorimetry (ITC) and surface plasmon resonance (SPR) system. Based on physicochemical data, we then reevaluated the metabolically beneficial effects of telmisartan in cultured murine adipocytes. ITC and SPR assays demonstrated that telmisartan exhibited the highest affinity of the ARBs tested. Distribution coefficient and parallel artificial membrane permeability assays were used to assess lipophilicity and cell permeability, for which telmisartan exhibited the highest levels of both. We next examined the effect of each ARB on insulin-mediated glucose metabolism in 3T3-L1 preadipocytes. To investigate the impact on adipogenesis, 3T3-L1 preadipocytes were differentiated with each ARB in addition to standard inducers of differentiation for adipogenesis. Telmisartan dose-dependently facilitated adipogenesis and markedly augmented the mRNA expression of adipocyte fatty acid-binding protein (aP2), accompanied by an increase in the uptake of 2-deoxyglucose and protein expression of glucose transporter 4 (GLUT4). In contrast, other ARBs showed only marginal effects in these experiments. In accordance with its highest affinity of binding for PPARγ as well as the highest cell permeability, telmisartan superbly activates PPARγ among the ARBs tested, thereby providing a fresh avenue for treating hypertensive patients with metabolic derangement. PMID:24424487

  16. Peroxisome proliferator activated receptor-γ agonists protect oligodendrocyte progenitors against tumor necrosis factor-alpha-induced damage: Effects on mitochondrial functions and differentiation.

    PubMed

    De Nuccio, C; Bernardo, A; Cruciani, C; De Simone, R; Visentin, S; Minghetti, L

    2015-09-01

    The activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPAR-γ) is known to exert anti-inflammatory and neuroprotective effects and PPAR-γ agonists are considered potential therapeutic agents in brain diseases including those affecting myelin. In demyelinating diseases such as multiple sclerosis (MS), inflammation is one of the causes of myelin and axonal damage. Oligodendrocyte (OL) differentiation is highly dependent on mitochondria, which are major targets of inflammatory insult. Here we show that PPAR-γ agonists protect OL progenitors against the maturational arrest induced by the inflammatory cytokine TNF-α by affecting mitochondrial functions. We demonstrate that the inhibition of OL differentiation by TNF-α is associated with i) increased mitochondrial superoxide production; ii) decreased mitochondrial membrane potential (mMP); and iii) decreased ADP-induced Ca(2+) oscillations, which we previously showed to be dependent on efficient mitochondria. The TNF-α effects were comparable to those of the mitochondrial toxin rotenone, further suggesting that TNF-α damage is mediated by mitochondrial function impairment. PPAR-γ agonists protected OL progenitors against the inhibitory activities of both TNF-α and rotenone on mMP, mitochondrial ROS production, Ca(2+) oscillations and OL differentiation. Finally, the PPAR-γ agonist pioglitazone increased the expression of PGC-1α (a mitochondrial biogenesis master regulator), UCP2 (a mitochondrial protein known to reduce ROS production), and cytochrome oxidase subunit COX1. These findings confirm the central role of mitochondria in OL differentiation and point to mitochondria as major targets of PPAR-γ agonist protection against TNF-α damage. PMID:26210873

  17. Metabolites related to gut bacterial metabolism, peroxisome proliferator-activated receptor-alpha activation, and insulin sensitivity are associated with physical function in functionally-limited older adults.

    PubMed

    Lustgarten, Michael S; Price, Lori L; Chalé, Angela; Fielding, Roger A

    2014-10-01

    Identification of mechanisms underlying physical function will be important for addressing the growing challenge that health care will face with physical disablement in the expanding aging population. Therefore, the goals of the current study were to use metabolic profiling to provide insight into biologic mechanisms that may underlie physical function by examining the association between baseline and the 6-month change in serum mass spectrometry-obtained amino acids, fatty acids, and acylcarnitines with baseline and the 6-month change in muscle strength (leg press one repetition maximum divided by total lean mass, LP/Lean), lower extremity function [short physical performance battery (SPPB)], and mobility (400 m gait speed, 400-m), in response to 6 months of a combined resistance exercise and nutritional supplementation (whey protein or placebo) intervention in functionally-limited older adults (SPPB ≤ 10; 70-85 years, N = 73). Metabolites related to gut bacterial metabolism (cinnamoylglycine, phenol sulfate, p-cresol sulfate, 3-indoxyl sulfate, serotonin, N-methylproline, hydrocinnamate, dimethylglycine, trans-urocanate, valerate) that are altered in response to peroxisome proliferator-activated receptor-alpha (PPAR-α) activation (α-hydroxyisocaproate, α-hydroxyisovalerate, 2-hydroxy-3-methylvalerate, indolelactate, serotonin, 2-hydroxypalmitate, glutarylcarnitine, isobutyrylcarnitine, cinnamoylglycine) and that are related to insulin sensitivity (monounsaturated fatty acids: 5-dodecenoate, myristoleate, palmitoleate; γ-glutamylamino acids: γ-glutamylglutamine, γ-glutamylalanine, γ-glutamylmethionine, γ-glutamyltyrosine; branched-chain amino acids: leucine, isoleucine, valine) were associated with function at baseline, with the 6-month change in function or were identified in backward elimination regression predictive models. Collectively, these data suggest that gut microbial metabolism, PPAR-α activation, and insulin sensitivity may be involved in

  18. Soluble epoxide hydrolase inhibition and peroxisome proliferator activated receptor γ agonist improve vascular function and decrease renal injury in hypertensive obese rats.

    PubMed

    Imig, John D; Walsh, Katie A; Hye Khan, Md Abdul; Nagasawa, Tasuku; Cherian-Shaw, Mary; Shaw, Sean M; Hammock, Bruce D

    2012-12-01

    Cardiometabolic syndrome occurs with obesity and consists of pathophysiological factors that increase the risk for cardiovascular events. Soluble epoxide hydrolase inhibition (sEHi) is a novel therapeutic approach that exerts renal and cardiovascular protection. Although sEHi as a therapeutic approach is promising, it could be more effective for the treatment of cardiometabolic syndrome when combined with peroxisome proliferator activated receptor γ (PPARγ) agonists. We hypothesized that the PPARγ agonist, rosiglitazone in combination with a sEHi (tAUCB) will provide synergistic actions to decrease blood pressure, improve vascular function, decrease inflammation, and prevent renal damage in spontaneously hypertensive obese rats (SHROB). SHROB were treated with rosiglitazone, tAUCB or the combination of tAUCB and rosiglitazone for four-weeks and compared with spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Blood pressure increased in SHROB (164 ± 7 mmHg) and decreased 10 mmHg when treated with rosiglitazone, tAUCB, or tAUCB and rosiglitazone. Mesenteric artery dilation to the K(ATP) channel opener pinacidil was attenuated in SHROB (E(Max) = 77 ± 7%), compared with WKY (E(Max) = 115 ± 19) and SHR (E(Max) = 93 ± 12%). Vasodilation to pinacidil was improved by rosiglitazone (E(Max) = 92 ± 14%) but not tAUCB. Renal macrophage infiltration increased in SHROB and significantly decreased with rosiglitazone or tAUCB and rosiglitazone treatment. Albuminuria was increased in SHROB (90 ± 20 mg/d) and was significantly decreased by the combination of tAUCB and rosiglitazone (37 ± 9 mg/d). Glomerular injury in SHROB was also significantly decreased by tAUCB and rosiglitazone. These results indicate that even though sEHi or PPARγ agonist have benefits when used individually, the combination is more beneficial for the multidisease features in cardiometabolic syndrome.

  19. Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

    PubMed

    Lakshmi, Sowmya P; Reddy, Aravind T; Zhang, Yingze; Sciurba, Frank C; Mallampalli, Rama K; Duncan, Steven R; Reddy, Raju C

    2014-03-01

    Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that down-regulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.

  20. Effect of alkyl glycerophosphate on the activation of peroxisome proliferator-activated receptor gamma and glucose uptake in C2C12 cells

    SciTech Connect

    Tsukahara, Tamotsu; Haniu, Hisao; Matsuda, Yoshikazu

    2013-04-12

    Highlights: •Alkyl-LPA specifically interacts with PPARγ. •Alkyl-LPA treatments induces lipid accumulation in C2C12 cells. •Alkyl-LPA enhanced glucose uptake in C2C12 cells. •Alkyl-LPA-treated C2C12 cells express increased amounts of GLUT4 mRNA. •Alkyl-LPA is a novel therapeutic agent that can be used for the treatment of obesity and diabetes. -- Abstract: Studies on the effects of lipids on skeletal muscle cells rarely examine the effects of lysophospholipids. Through our recent studies, we identified select forms of phospholipids, such as alkyl-LPA, as ligands for the intracellular receptor peroxisome proliferator-activated receptor gamma (PPARγ). PPARγ is a nuclear hormone receptor implicated in many human diseases, including diabetes and obesity. We previously showed that alkyl-LPA is a specific agonist of PPARγ. However, the mechanism by which the alkyl-LPA–PPARγ axis affects skeletal muscle cells is poorly defined. Our objective in the present study was to determine whether alkyl-LPA and PPARγ activation promotes glucose uptake in skeletal muscle cells. Our findings indicate that PPARγ1 mRNA is more abundant than PPARγ2 mRNA in C2C12 cells. We showed that alkyl-LPA (3 μM) significantly activated PPARγ and increased intracellular glucose levels in skeletal muscle cells. We also showed that incubation of C2C12 cells with alkyl-LPA led to lipid accumulation in the cells. These findings suggest that alkyl-LPA activates PPARγ and stimulates glucose uptake in the absence of insulin in C2C12 cells. This may contribute to the plasma glucose-lowering effect in the treatment of insulin resistance.

  1. The activation of peroxisome proliferator-activated receptor γ is regulated by Krüppel-like transcription factors 6 & 9 under steatotic conditions

    SciTech Connect

    Escalona-Nandez, Ivonne; Guerrero-Escalera, Dafne; Estanes-Hernández, Alma; Ortíz-Ortega, Victor; Tovar, Armando R.; Pérez-Monter, Carlos

    2015-03-20

    Liver steatosis is characterised by lipid droplet deposition in hepatocytes that can leads to an inflammatory and fibrotic phenotype. Peroxisome proliferator-activated receptors (PPARs) play key roles in energetic homeostasis by regulating lipid metabolism in hepatic tissue. In adipose tissue PPARγ regulates the adipocyte differentiation by promoting the expression of lipid-associated genes. Within the liver PPARγ is up-regulated under steatotic conditions; however, which transcription factors participate in its expression is not completely understood. Krüppel-like transcription factors (KLFs) regulate various cellular mechanisms, such as cell proliferation and differentiation. KLFs are key components of adipogenesis by regulating the expression of PPARγ and other proteins such as the C-terminal enhancer binding protein (C/EBP). Here, we demonstrate that the transcript levels of Klf6, Klf9 and Pparγ are increased in response to a steatotic insult in vitro. Chromatin immunoprecipitation (ChIp) experiments showed that klf6 and klf9 are actively recruited to the Pparγ promoter region under these conditions. Accordingly, the loss-of-function experiments reduced cytoplasmic triglyceride accumulation. Here, we demonstrated that KLF6 and KLF9 proteins directly regulate PPARγ expression under steatotic conditions. - Highlights: • Palmitic acid promotes expression of KlF6 & KLF9 in HepG2 cells. • KLF6 and KLF9 promote the expression of PPARγ in response to palmitic acid. • Binding of KLF6 and KLF9 to the PPARγ promoter promotes steatosis in HepG2 cells. • KLF6 and KLF9 loss-of function diminishes the steatosis in HepG2 cells.

  2. Expression of Peroxisome Proliferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death1

    PubMed Central

    Guan, You-Fei; Zhang, Ya-Hua; Breyer, Richard M; Davis, Linda; Breyer, Matthew D

    1999-01-01

    Abstract The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARγ, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARγ agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRα ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPARγ activators, ciglitazone and 15-deoxy-Δ2,14-PGJ2 (15dPGJ2). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, P21WAF1/CIP1 and p16INK4, and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARγ target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARγ is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers. PMID:10935488

  3. Ligand and coactivator identity determines the requirement of the charge clamp for coactivation of the peroxisome proliferator-activated receptor gamma.

    PubMed

    Wu, Yifei; Chin, William W; Wang, Yong; Burris, Thomas P

    2003-03-01

    The activation function 2 (AF-2)-dependent recruitment of coactivator is essential for gene activation by nuclear receptors. We show that the peroxisome proliferator-activated receptor gamma (PPARgamma) (NR1C3) coactivator-1 (PGC-1) requires both the intact AF-2 domain of PPARgamma and the LXXLL domain of PGC-1 for ligand-dependent and ligand-independent interaction and coactivation. Although the AF-2 domain of PPARgamma is absolutely required for PGC-1-mediated coactivation, this coactivator displayed a unique lack of requirement for the charge clamp of the ligand-binding domain of the receptor that is thought to be essential for LXXLL motif recognition. The mutation of a single serine residue adjacent to the core LXXLL motif of PGC-1 led to restoration of the typical charge clamp requirement. Thus, the unique structural features of the PGC-1 LXXLL motif appear to mediate an atypical mode of interaction with PPARgamma. Unexpectedly, we discovered that various ligands display variability in terms of their requirement for the charge clamp of PPARgamma for coactivation by PGC-1. This ligand-selective variable requirement for the charge clamp was coactivator-specific. Thus, distinct structural determinants, which may be unique for a particular ligand, are utilized by the receptor to recognize the coactivator. Our data suggest that even subtle differences in ligand structure are perceived by the receptor and translated into a unique display of the coactivator-binding surface of the ligand-binding domain, allowing for differential recognition of coactivators that may underlie distinct pharmacological profiles observed for ligands of a particular nuclear receptor.

  4. Cardiac lipin 1 expression is regulated by the peroxisome proliferator activated receptor γ coactivator 1α/estrogen related receptor axis.

    PubMed

    Mitra, Mayurranjan S; Schilling, Joel D; Wang, Xiaowei; Jay, Patrick Y; Huss, Janice M; Su, Xiong; Finck, Brian N

    2011-07-01

    Lipin family proteins (lipin 1, 2, and 3) are bifunctional intracellular proteins that regulate metabolism by acting as coregulators of DNA-bound transcription factors and also dephosphorylate phosphatidate to form diacylglycerol [phosphatidate phosphohydrolase activity] in the triglyceride synthesis pathway. Herein, we report that lipin 1 is enriched in heart and that hearts of mice lacking lipin 1 (fld mice) exhibit accumulation of phosphatidate. We also demonstrate that the expression of the gene encoding lipin 1 (Lpin1) is under the control of the estrogen-related receptors (ERRs) and their coactivator the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). PGC-1α, ERRα, or ERRγ overexpression increased Lpin1 transcription in cultured ventricular myocytes and the ERRs were associated with response elements in the first intron of the Lpin1 gene. Concomitant RNAi-mediated knockdown of ERRα and ERRγ abrogated the induction of lipin 1 expression by PGC-1α overexpression. Consistent with these data, 3-fold overexpression of PGC-1α in intact myocardium of transgenic mice increased cardiac lipin 1 and ERRα/γ expression. Similarly, injection of the β2-adrenergic agonist clenbuterol induced PGC-1α and lipin 1 expression, and the induction in lipin 1 after clenbuterol occurred in a PGC-1α-dependent manner. In contrast, expression of PGC-1α, ERRα, ERRγ, and lipin 1 was down-regulated in failing heart. Cardiac phosphatidic acid phosphohydrolase activity was also diminished, while cardiac phosphatidate content was increased, in failing heart. Collectively, these data suggest that lipin 1 is the principal lipin protein in the myocardium and is regulated in response to physiologic and pathologic stimuli that impact cardiac metabolism. PMID:21549711

  5. Mechanism-based inhibitory and peroxisome proliferator-activated receptor α-dependent modulating effects of silybin on principal hepatic drug-metabolizing enzymes.

    PubMed

    Wang, Hong; Yan, Tingting; Xie, Yuan; Zhao, Min; Che, Yuan; Zhang, Jun; Liu, Huiying; Cao, Lijuan; Cheng, Xuefang; Xie, Yang; Li, Feiyan; Qi, Qu; Wang, Guangji; Hao, Haiping

    2015-04-01

    Silybin, a major pharmacologically active compound in silymarin, has been widely used in combination with other prescriptions in the clinic to treat hepatitis and a host of other diseases. Previous studies suggested that silybin is a potential inhibitor of multiple drug-metabolizing enzymes (DMEs); however, the in vitro to in vivo translation and the mechanisms involved remain established. The aim of this study was to provide a mechanistic understanding of the regulatory effects of silybin on principal DMEs. Silybin (50 or 150 mg/kg/d) was administered to mice for a consecutive 14 days. The plasma and hepatic exposure of silybin were detected; the mRNA, protein levels, and enzyme activities of principal DMEs were determined. The results demonstrated that the enzyme activities of CYP1A2, CYP2C, CYP3A11, and UGT1A1 were significantly repressed, whereas little alteration of the mRNA and protein levels was observed. Silybin inhibits these DMEs in a mechanism-based and/or substrate-competitive manner. More importantly, silybin was found to be a weak agonist of peroxisome proliferator-activated receptor (PPAR)α, as evidenced from the molecular docking, reporter gene assay, and the targeting gene expression analysis. However, silybin could significantly compromise the activation of PPARα by fenofibrate, characterized with significantly repressed expression of PPARα targeting genes, including L-FABP, ACOX1, and UGT1A6. This study suggests that silybin, despite its low bioavailability, may inhibit enzyme activities of multiple DMEs in a mechanism-based mode, and more importantly, may confer significant drug-drug interaction with PPARα agonists via the repression of PPARα activation in a competitive mode. PMID:25587127

  6. The Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma (PPARG) gene in relation to obesity and metabolic phenotypes in a Taiwanese population.

    PubMed

    Hsiao, Tun-Jen; Lin, Eugene

    2015-04-01

    Obesity is considered as an important public health problem in the world. Although the association of a common single nucleotide polymorphism (SNP), rs1801282 (Pro12Ala), in the peroxisome proliferator-activated receptor gamma (PPARG) gene with obesity has been reported in various populations, these data are not conclusive. This study aimed to reassess whether the PPARG rs1801282 SNP is linked with obesity and obesity-related metabolic traits in a Taiwanese population. A total of 674 Taiwanese subjects with general health examinations were genotyped. The rs1801282 genotype was determined by the Taqman SNP genotyping assay. Obesity-related metabolic traits such as triglyceride, waist circumference, systolic and diastolic blood pressure, total cholesterol, and fasting glucose were measured. The PPARG rs1801282 SNP did not exhibit any significant association with obesity among the complete sample population. However, sex-stratified analyses revealed an effect on overweight in female participants where the carriers of the combined CG and GG genotypes had a higher risk to overweight than those with the CC homozygotes (OR=4.05; 95% CI=1.28-12.83; P=0.017). Compared to the carriers of CC homozygotes, BMI was significantly higher for the carriers of the combined CG and GG genotypes in the female subjects (24.4±3.7 vs. 23.5±3.8 kg/m2; P=0.033). In addition, the carriers of the CC homozygotes had a higher total cholesterol level than those with the combined CG and GG genotypes in the female subjects (197.0±37.3 vs. 180.7±33.7 mg/dl; P=0.026). Our study indicates that PPARG rs1801282 may significantly predict overweight, BMI, and total cholesterol in female but not male Taiwanese subjects.

  7. Peroxisome Proliferator-Activated Receptor γ Controls Ingestive Behavior, Agouti-Related Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus

    PubMed Central

    Garretson, John T.; Teubner, Brett J.W.; Grove, Kevin L.; Vazdarjanova, Almira; Ryu, Vitaly

    2015-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is clinically targeted for type II diabetes treatment; however, rosiglitazone (ROSI), a PPARγ agonist, increases food intake and body/fat mass as side-effects. Mechanisms for these effects and the role of PPARγ in feeding are not understood. Therefore, we tested this role in Siberian hamsters, a model of human energy balance, and C57BL/6 mice. We tested the following: (1) how ROSI and/or GW9662 (2-chloro-5-nitro-N-phenylbenzamide; PPARγ antagonist) injected intraperitoneally or into the third ventricle (3V) affected Siberian hamster feeding behaviors; (2) whether food deprivation (FD) co-increases agouti-related protein (AgRP) and PPARγ mRNA expression in Siberian hamsters and mice; (3) whether intraperitoneally administered ROSI increases AgRP and NPY in ad libitum-fed animals; (4) whether intraperitoneally administered PPARγ antagonism blocks FD-induced increases in AgRP and NPY; and finally, (5) whether intraperitoneally administered PPARγ modulation affects plasma ghrelin. Third ventricular and intraperitoneally administered ROSI increased food hoarding and intake for 7 d, an effect attenuated by 3V GW9662, and also prevented (intraperitoneal) FD-induced feeding. FD hamsters and mice increased AgRP within the arcuate hypothalamic nucleus with concomitant increases in PPARγ exclusively within AgRP/NPY neurons. ROSI increased AgRP and NPY similarly to FD, and GW9662 prevented FD-induced increases in AgRP and NPY in both species. Neither ROSI nor GW9662 affected plasma ghrelin. Thus, we demonstrated that PPARγ activation is sufficient to trigger food hoarding/intake, increase AgRP/NPY, and possibly is necessary for FD-induced increases in feeding and AgRP/NPY. These findings provide initial evidence that FD-induced increases in AgRP/NPY may be a direct PPARγ-dependent process that controls ingestive behaviors. PMID:25788674

  8. α-Lipoic acid up-regulates expression of peroxisome proliferator-activated receptor β in skeletal muscle: involvement of the JNK signaling pathway.

    PubMed

    Rousseau, Anne-Sophie; Sibille, Brigitte; Murdaca, Joseph; Mothe-Satney, Isabelle; Grimaldi, Paul A; Neels, Jaap G

    2016-03-01

    We hypothesized that α-lipoic acid (α-LA) might interact with the transcriptional control of peroxisome proliferator-activated receptor (PPAR)β in skeletal muscle. Molecular mechanisms were investigated using differentiated C2C12 myotubes treated with α-LA and/or PPARβ agonist GW0742. In vivo studies with 3-mo-old C57Bl6 mice were realized: voluntary wheel running (VWR) training (7 wk), and a 6 wk diet containing (or not) α-LA (0.25% wt/wt). This last condition was combined with (or not) 1 bout of treadmill exercise (18 m/min for 1 h). Using a reporter assay, we demonstrate that α-LA is not an agonist of PPARβ but regulates PPARβ target gene expression through an active PPARβ pathway. GW0742-induced pyruvate dehydrogenase kinase 4 mRNA is potentiated by α-LA. In C2C12, α-LA lowers the activation of the JNK signaling pathway and increases PPARβ mRNA and protein levels (2-fold) to the same extent as with the JNK inhibitor SP600125. Similarly to VWR training effect, PPARβ expression increases (2-fold) in vastus lateralis of animals fed an α-LA-enriched diet. However, α-LA treatment does not further stimulate the adaptive up-regulation of PPARβ observed in response to 1 bout of exercise. We have identified a novel mechanism of regulation of PPARβ expression/action in skeletal muscle with potential physiologic application through the action of α-LA, involving the JNK pathway.

  9. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ.

    PubMed

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell'Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE((-/-)) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser(1177)-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE((-/-)) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser(1177)-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  10. Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR) family.

    PubMed

    Weidner, Christopher; Wowro, Sylvia J; Rousseau, Morten; Freiwald, Anja; Kodelja, Vitam; Abdel-Aziz, Heba; Kelber, Olaf; Sauer, Sascha

    2013-01-01

    Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders. PMID:24265809

  11. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ

    PubMed Central

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell’Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE(-/-) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser1177-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE(-/-) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser1177-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD. PMID:27679746

  12. Peroxisome-proliferator activator receptor-gamma activation decreases attachment of endometrial cells to peritoneal mesothelial cells in an in vitro model of the early endometriotic lesion.

    PubMed

    Kavoussi, S K; Witz, C A; Binkley, P A; Nair, A S; Lebovic, D I

    2009-10-01

    The aim of this study was to investigate whether peroxisome proliferator-activated receptor (PPAR)-gamma activation has an effect on the attachment of endometrial cells to peritoneal mesothelial cells in a well-established in vitro model of the early endometriotic lesion. The endometrial epithelial cell line EM42 and mesothelial cell line LP9 were used for this study. EM42 cells, LP9 cells or both were treated with the PPAR-gamma agonist ciglitazone (CTZ) at varying concentrations (10, 20 and 40 microM) x 48 h with subsequent co-culture of EM42 and LP9 cells. The rate of EM42 attachment and invasion through LP9 cells was then assessed and compared with control (EM42 and LP9 cells co-cultured without prior treatment with CTZ). Next, attachment of CTZ-treated and untreated EM42 cells to hyaluronic acid (HA), a cell adhesion molecule (CAM) on peritoneal mesothelial cells, were assessed. Although there was no difference in EM42 attachment when LP9 cells alone were treated with CTZ, treatment of EM42 cells with 40 microM CTZ decreased EM42 attachment to LP9 cells by 27% (P < 0.01). Treatment of both EM42 and LP9 cells with 40 microM CTZ decreased EM42 attachment to LP9 by 37% (P < 0.01). Treatment of EM42 cells with 40 microM CTZ decreased attachment to HA by 66% (P = 0.056). CTZ did not decrease invasion of EM42 cells through the LP9 monolayer. CTZ may inhibit EM42 cell proliferation. In conclusion, CTZ significantly decreased EM42 attachment to LP9 cells and HA in an in vitro model of the early endometriotic lesion. PMID:19643817

  13. Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy.

    PubMed

    Hirano, Ken-ichi; Tanaka, Tatsuya; Ikeda, Yoshihiko; Yamaguchi, Satoshi; Zaima, Nobuhiro; Kobayashi, Kazuhiro; Suzuki, Akira; Sakata, Yasuhiko; Sakata, Yasushi; Kobayashi, Kunihisa; Toda, Tatsushi; Fukushima, Norihide; Ishibashi-Ueda, Hatsue; Tavian, Daniela; Nagasaka, Hironori; Hui, Shu-Ping; Chiba, Hitoshi; Sawa, Yoshiki; Hori, Masatsugu

    2014-01-10

    Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, "Triglyceride deposit cardiomyovasculopathy (TGCV)". Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5' splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules' lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients' passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG is defective, the marked up-regulation of PPARγ and related genes may lead to increased uptake of LCFAs, the substrates for TG synthesis. This potentially vicious cycle of LCFAs could explain the massive accumulation of TG and severe clinical course for this rare

  14. Antidiabetic Effects of Chamomile Flowers Extract in Obese Mice through Transcriptional Stimulation of Nutrient Sensors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family

    PubMed Central

    Weidner, Christopher; Wowro, Sylvia J.; Rousseau, Morten; Freiwald, Anja; Kodelja, Vitam; Abdel-Aziz, Heba; Kelber, Olaf; Sauer, Sascha

    2013-01-01

    Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders. PMID:24265809

  15. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator-activated receptor-gamma mutations associated with diabetes.

    PubMed

    Li, Gang; Leff, Todd

    2007-04-01

    The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARgamma have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARgamma allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARgamma mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARgamma to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARgamma bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

  16. Evidence for a luteotropic role of peroxisome proliferator-activated receptor gamma: expression and in vitro effects on enzymatic and hormonal activities in corpora lutea of pseudopregnant rabbits.

    PubMed

    Zerani, Massimo; Maranesi, Margherita; Brecchia, Gabriele; Gobbetti, Anna; Boiti, Cristiano; Parillo, Francesco

    2013-03-01

    The expression of peroxisome proliferator-activated receptor gamma (PPARgamma) and its role in corpora lutea (CL) function were studied in pseudopregnant rabbits. Corpora lutea were collected at an early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. Immunohistochemistry found evidence for the presence of PPARgamma in the perinuclear cytoplasm and nucleus of all the luteal cells; immunoreactivity decreased from the early to the late stage, with immunonegativity of the nuclei of late stage CL. PPARgamma mRNA transcript was expressed in all the luteal stages with the lowest level in the late stage. In CL cultured in vitro, the PPARgamma agonist (15-deoxy delta12,14 prostaglandin J2 [15d-PGJ2], 200 nM) increased and the antagonist (T0070907, 50 nM) decreased progesterone secretion at early and midluteal stages, whereas 15d-PGJ2 reduced and T0070907 increased PGF2alpha at the same stages. Prostaglandin-endoperoxide synthase 2 (PTGS2) activity was reduced by 15d-PGJ2 and increased by T0070907 in CL of early and midluteal stages. Conversely, 15d-PGJ2 increased and T0070907 reduced 3beta-hydroxysteroid dehydrogenase (3beta-HSD) activity in early and midluteal stage CL. PGE2 in vitro secretion as well as PTGS1 and 20alpha-HSD enzymatic activities were not affected by 15d-PGJ2 and T0070907 in any CL types. These results indicate that PPARgamma plays a luteotropic role in pseudopregnant rabbits, through PTGS2 down-regulation and 3beta-HSD up-regulation, with a consequent PGF2alpha decrease and progesterone increase.

  17. In vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate on pseudopregnant rabbit corpora lutea: possible involvement of peroxisome proliferator-activated receptor gamma.

    PubMed

    Parillo, Francesco; Maranesi, Margherita; Brecchia, Gabriele; Gobbetti, Anna; Boiti, Cristiano; Zerani, Massimo

    2014-02-01

    The in vivo chronic and in vitro acute effects of di(2-ethylhexyl) phthalate (DEHP) on the reproductive function of peroxisome proliferator-activated receptor gamma (PPARG) were studied in rabbit corpora lutea (CL) at early stage (Day 4), midstage (Day 9), and late stage (Day 13) of pseudopregnancy. The rabbits were in vivo treated with DEHP for 15 days before induction of pseudopregnancy. Immunohistochemistry provided evidence for the presence of PPARG, prostaglandin endoperoxide synthase 1 (PTGS1), PTGS2, prostaglandin E2-9-ketoreductase (PGE2-9-K), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in all the luteal cells during pseudopregnancy. DEHP decreased progesterone plasma levels and CL production in all the luteal stages and PPARG protein and gene expressions in early and mid-CL. DEHP in vivo treatment reduced PTGS2 protein expression at the late stage and that of PGE2-9-K at all the stages, whereas PTGS1 and 3beta-HSD were not affected. In in vitro cultured CL, DEHP alone, the PPARG antagonist T0070907 alone, or DEHP plus T0070907 diminished progesterone production and 3beta-HSD activity and increased PGF2alpha and PTGS2 in early and mid-CL, whereas DEHP plus the PPARG agonist 15d-PGJ2 did not affect these hormones and enzymes. All the in vitro treatments did not affect PGE2 secretion as well as PTGS1 and PGE2-9-K enzymatic activities in all the luteal stages. These results provided evidence that DEHP favors functional luteolysis of pseudopregnant rabbit CL, with a mechanism that seems to involve PPARG expression down-regulation, an increase of PTGS2 activity and prostaglandin F2alpha secretion, 3beta-HSD down-regulation, and decrease in progesterone.

  18. Cloning of the rat pyruvate dehydrogenase kinase 4 gene promoter: activation of pyruvate dehydrogenase kinase 4 by the peroxisome proliferator-activated receptor gamma coactivator.

    PubMed

    Ma, Ke; Zhang, Yi; Elam, Marshall B; Cook, George A; Park, Edwards A

    2005-08-19

    The pyruvate dehydrogenase complex catalyzes the conversion of pyruvate to acetyl-CoA in mitochondria and is a key regulatory enzyme in the metabolism of glucose to acetyl-CoA. Phosphorylation of pyruvate dehydrogenase by the pyruvate dehydrogenase kinases (PDK) inhibits pyruvate dehydrogenase complex activity. There are four PDK isoforms, and expression of PDK4 and PDK2 genes is elevated in starvation and diabetes, allowing glucose to be conserved while fatty acid oxidation is increased. In these studies we have investigated the transcriptional mechanisms by which the expression of the PDK4 gene is increased. The peroxisome proliferator-activated receptor gamma coactivator (PGC-1alpha) stimulates the expression of genes involved in hepatic gluconeogenesis and mitochondrial fatty acid oxidation. We have found that PGC-1alpha will induce the expression of both the PDK2 and PDK4 genes in primary rat hepatocytes and ventricular myocytes. We cloned the promoter for the rat PDK4 gene. Hepatic nuclear factor 4 (HNF4), which activates many genes in the liver, will induce PDK4 expression. Although HNF4 and PGC-1alpha interact to stimulate several genes encoding gluconeogenic enzymes, the induction of PDK4 does not involve interactions of PGC-1alpha with HNF4. Using the chromatin immunoprecipitation assay, we have demonstrated that HNF4 and PGC-1alpha are associated with the PDK4 gene in vivo. Our data suggest that by inducing PDK genes PGC-1alpha will direct pyruvate away from metabolism into acetyl-CoA and toward the formation of oxaloacetate and into the gluconeogenic pathway. PMID:15967803

  19. Three members of the human pyruvate dehydrogenase kinase gene family are direct targets of the peroxisome proliferator-activated receptor beta/delta.

    PubMed

    Degenhardt, Tatjana; Saramäki, Anna; Malinen, Marjo; Rieck, Markus; Väisänen, Sami; Huotari, Anne; Herzig, Karl-Heinz; Müller, Rolf; Carlberg, Carsten

    2007-09-14

    The nuclear receptors peroxisome proliferator-activated receptors (PPARs) are known for their critical role in the metabolic syndrome. Here, we show that they are direct regulators of the family of pyruvate dehydrogenase kinase (PDK) genes, whose products act as metabolic homeostats in sensing hunger and satiety levels in key metabolic tissues by modulating the activity of the pyruvate dehydrogenase complex. Mis-regulation of this tightly controlled network may lead to hyperglycemia. In human embryonal kidney cells we found the mRNA expression of PDK2, PDK3 and PDK4 to be under direct primary control of PPAR ligands, and in normal mouse kidney tissue Pdk2 and Pdk4 are PPAR targets. Both, treatment of HEK cells with PPARbeta/delta-specific siRNA and the genetic disruption of the Pparbeta/delta gene in mouse fibroblasts resulted in reduced expression of Pdk genes and abolition of induction by PPARbeta/delta ligands. These findings suggest that PPARbeta/delta is a key regulator of PDK genes, in particular the PDK4/Pdk4 gene. In silico analysis of the human PDK genes revealed two candidate PPAR response elements in the PDK2 gene, five in the PDK3 gene and two in the PDK4 gene, but none in the PDK1 gene. For seven of these sites we could demonstrate both PPARbeta/delta ligand responsiveness in context of their chromatin region and simultaneous association of PPARbeta/delta with its functional partner proteins, such as retinoidXreceptor, co-activator and mediator proteins and phosphorylated RNA polymerase II. In conclusion, PDK2, PDK3 and PDK4 are primary PPARbeta/delta target genes in humans underlining the importance of the receptor in the control of metabolism. PMID:17669420

  20. PPARα (Peroxisome Proliferator-activated Receptor α) Activation Reduces Hepatic CEACAM1 Protein Expression to Regulate Fatty Acid Oxidation during Fasting-refeeding Transition.

    PubMed

    Ramakrishnan, Sadeesh K; Khuder, Saja S; Al-Share, Qusai Y; Russo, Lucia; Abdallah, Simon L; Patel, Payal R; Heinrich, Garrett; Muturi, Harrison T; Mopidevi, Brahma R; Oyarce, Ana Maria; Shah, Yatrik M; Sanchez, Edwin R; Najjar, Sonia M

    2016-04-01

    Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is expressed at high levels in the hepatocyte, consistent with its role in promoting insulin clearance in liver. CEACAM1 also mediates a negative acute effect of insulin on fatty acid synthase activity. Western blot analysis reveals lower hepatic CEACAM1 expression during fasting. Treating of rat hepatoma FAO cells with Wy14,643, an agonist of peroxisome proliferator-activated receptor α (PPARα), rapidly reduces Ceacam1 mRNA and CEACAM1 protein levels within 1 and 2 h, respectively. Luciferase reporter assay shows a decrease in the promoter activity of both rat and mouse genes by Pparα activation, and 5'-deletion and block substitution analyses reveal that the Pparα response element between nucleotides -557 and -543 is required for regulation of the mouse promoter activity. Chromatin immunoprecipitation analysis demonstrates binding of liganded Pparα toCeacam1promoter in liver lysates ofPparα(+/+), but notPparα(-/-)mice fed a Wy14,643-supplemented chow diet. Consequently, Wy14,643 feeding reduces hepatic Ceacam1 mRNA and CEACAM1 protein levels, thus decreasing insulin clearance to compensate for compromised insulin secretion and maintain glucose homeostasis and insulin sensitivity in wild-type mice. Together, the data show that the low hepatic CEACAM1 expression at fasting is mediated by Pparα-dependent mechanisms. Changes in CEACAM1 expression contribute to the coordination of fatty acid oxidation and insulin action in the fasting-refeeding transition.

  1. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha activation of CYP7A1 during food restriction and diabetes is still inhibited by small heterodimer partner.

    PubMed

    Shin, Dong-Ju; Osborne, Timothy F

    2008-05-30

    Cholesterol 7alpha-hydroxylase (CYP7A1) catalyzes the rate-limiting step in the classic pathway of hepatic bile acid biosynthesis from cholesterol. During fasting and in type I diabetes, elevated levels of peroxisome proliferator-activated receptor gamma-coactivator-1alpha (PGC-1alpha) induce expression of the Cyp7A1 gene and overexpression of PGC-1alpha in hepatoma cells stimulates bile acid synthesis. Using Ad-PGC-1alpha-RNA interference to induce acute disruption of PGC-1alpha in mice, here we show that PGC-1alpha is necessary for fasting-mediated induction of CYP7A1. Co-immunoprecipitation and promoter activation studies reveal that the induction of CYP7A1 is mediated by direct interaction between PGC-1alpha and the AF2 domain of liver receptor homolog-1 (LRH-1). In contrast, the very similar PGC-1beta could not substitute for PGC-1alpha. We also show that transactivation of PGC-1alpha and LRH-1 is repressed by the small heterodimer partner (SHP). Treatment of mice with GW4064, a synthetic agonist for farnesoid X receptor, induced SHP expression and decreased both the recruitment of PGC-1alpha to the Cyp7A1 promoter and the fasting-induced expression of CYP7A1 mRNA. These data suggest that PGC-1alpha is an important co-activator for LRH-1 and that SHP targets the interaction between LRH-1 and PGC-1alpha to inhibit CYP7A1 expression. Overall, these studies provide further evidence for the important role of PGC-1alpha in bile acid homeostasis and suggest that pharmacological targeting of farnesoid X receptor in vivo can be used to reverse the increase in CYP7A1 associated with adverse metabolic conditions.

  2. Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium

    PubMed Central

    Oshida, Keiyu; Vasani, Naresh; Thomas, Russell S.; Applegate, Dawn; Rosen, Mitch; Abbott, Barbara; Lau, Christopher; Guo, Grace; Aleksunes, Lauren M.; Klaassen, Curtis; Corton, J. Christopher

    2015-01-01

    The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents increases liver cancer incidence, whereas suppression of PPARα activity leads to hepatocellular steatosis. Analytical approaches were developed to identify biosets (i.e., gene expression differences between two conditions) in a genomic database in which PPARα activity was altered. A gene expression signature of 131 PPARα-dependent genes was built using microarray profiles from the livers of wild-type and PPARα-null mice after exposure to three structurally diverse PPARα activators (WY-14,643, fenofibrate and perfluorohexane sulfonate). A fold-change rank-based test (Running Fisher’s test (p-value ≤ 10-4)) was used to evaluate the similarity between the PPARα signature and a test set of 48 and 31 biosets positive or negative, respectively for PPARα activation; the test resulted in a balanced accuracy of 98%. The signature was then used to identify factors that activate or suppress PPARα in an annotated mouse liver/primary hepatocyte gene expression compendium of ~1850 biosets. In addition to the expected activation of PPARα by fibrate drugs, di(2-ethylhexyl) phthalate, and perfluorinated compounds, PPARα was activated by benzofuran, galactosamine, and TCDD and suppressed by hepatotoxins acetaminophen, lipopolysaccharide, silicon dioxide nanoparticles, and trovafloxacin. Additional factors that activate (fasting, caloric restriction) or suppress (infections) PPARα were also identified. This study 1) developed methods useful for future screening of environmental chemicals, 2) identified chemicals that activate or suppress PPARα, and 3) identified factors including diets and infections that modulate PPARα activity and would be hypothesized to affect chemical-induced PPAR

  3. Double di oxygenation by mouse 8S-lipoxygenase: Specific formation of a potent peroxisome proliferator-activated receptor {alpha} agonist

    SciTech Connect

    Jisaka, Mitsuo . E-mail: jisaka@life.shimane-u.ac.jp; Iwanaga, Chitose; Takahashi, Nobuyuki; Goto, Tsuyoshi; Kawada, Teruo; Yamamoto, Tatsuyuki; Ikeda, Izumi; Nishimura, Kohji; Nagaya, Tsutomu; Fushiki, Tohru; Yokota, Kazushige

    2005-12-09

    Mouse 8S-lipoxygenase (8-LOX) metabolizes arachidonic acid (AA) specifically to 8S-hydroperoxyeicosatetraenoic acid (8S-HPETE), which will be readily reduced under physiological circumstances to 8S-hydroxyeicosatetraenoic acid (8S-HETE), a natural agonist of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}). Here, we investigated whether 8-LOX could further oxygenate AA and whether the products could activate PPARs. The purified recombinant 8-LOX converted AA exclusively to 8S-HPETE and then to (8S,15S)-dihydroperoxy-5Z,9E,11Z,13E-eicosatetraenoic acid (8S,15S-diHPETE). The k {sub cat}/K {sub m} values for 8S-HPETE and AA were 3.3 x 10{sup 3} and 2.7 x 10{sup 4} M{sup -1} s{sup -1}, respectively. 8-LOX also dioxygenated 8S-HETE and 15S-H(P)ETE specifically to the corresponding 8S,15S-disubstituted derivatives. By contrast, 15-LOX-2, a human homologue of 8-LOX, produced 8S,15S-diH(P)ETE from 8S-H(P)ETE but not from AA nor 15S-H(P)ETE. 8S,15S-diHETE activated PPAR{alpha} more strongly than 8S-HETE did. The present results suggest that 8S,15S-diH(P)ETE as well as 8S-H(P)ETE would contribute to the physiological function of 8-LOX and also that 8-LOX can function as a potential 15-LOX.

  4. Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation

    SciTech Connect

    Yu, Jung Hwan; Lee, Yoo Jeong; Kim, Hyo Jung; Choi, Hyeonjin; Choi, Yoonjeong; Seok, Jo Woon; Kim, Jae-woo

    2015-05-08

    Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans. - Highlights: • PPARγ promotes MGAT1 expression in human primary hepatocytes. • PPARγ directly regulates MGAT1 promoter activity. • Human MGAT1 promoter has at least two PPARγ-binding elements. • Inhibition of MGAT1 expression attenuates hepatic lipid accumulation in humans.

  5. Angiotensin type 2-receptor (AT2R) activation induces hypotension in apolipoprotein E-deficient mice by activating peroxisome proliferator-activated receptor-γ

    PubMed Central

    Li, Ming; Tejada, Thor; Lambert, Jonathan P; Nicholson, Chad K; Yahiro, Eiji; Ambai, Vats T; Ali, Syeda F; Bradley, Eddie W; Graham, Robert M; Dell’Italia, Louis J; Calvert, John W; Naqvi, Nawazish

    2016-01-01

    Angiotensin II (Ang II) modulates blood pressure and atherosclerosis development through its vascular type-1 (AT1R) and type-2 (AT2R) receptors, which have opposing effects. AT2R activation produces hypotension, and is anti-atherogenic. Targeted overexpression of AT2Rs in vascular smooth muscle cells (VSMCs) indicates that these effects are due to increased nitric oxide (NO) generation. However, the role of endogenous VSMC AT2Rs in these events is unknown. Effect of 7-day low-dose Ang II-infusion (12 µg/kg/hr) on blood pressure was tested in 9-week-old apoE(-/-) mice fed a low or high cholesterol diet (LCD or HCD, respectively). Cardiac output was measured by echocardiography. Immunohistochemistry was performed to localize and quantify AT2Rs and p-Ser1177-endothelial nitric oxide synthase (eNOS) levels in the aortic arch. PD123319 and GW-9662 were used to selectively block the AT2R and peroxisome proliferator-activated receptor-γ (PPAR-γ), respectively. Ang II infusion decreased blood pressure by 12 mmHg (P < 0.001) in LCD/apoE(-/-) mice without altering cardiac output; a response blocked by PD123319. Although, AT2R stimulation neither activated eNOS (p-Ser1177-eNOS) nor changed plasma NO metabolites, it caused an ~6-fold increase in VSMC PPAR-γ levels (P < 0.001) and the AT2R-mediated hypotension was abolished by GW-9662. AT2R-mediated hypotension was also inhibited by HCD, which selectively decreased VSMC AT2R expression by ~6-fold (P < 0.01). These findings suggest a novel pathway for the Ang II/AT2R-mediated hypotensive response that involves PPAR-γ, and is down regulated by a HCD.

  6. Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer*

    PubMed Central

    Ramachandran, Lalitha; Manu, Kanjoormana Aryan; Shanmugam, Muthu K.; Li, Feng; Siveen, Kodappully Sivaraman; Vali, Shireen; Kapoor, Shweta; Abbasi, Taher; Surana, Rohit; Smoot, Duane T.; Ashktorab, Hassan; Tan, Patrick; Ahn, Kwang Seok; Yap, Chun Wei; Kumar, Alan Prem; Sethi, Gautam

    2012-01-01

    Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3′-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC. PMID:22992727

  7. Peroxisome proliferator-activated receptor gamma regulates expression of the anti-lipolytic G-protein-coupled receptor 81 (GPR81/Gpr81).

    PubMed

    Jeninga, Ellen H; Bugge, Anne; Nielsen, Ronni; Kersten, Sander; Hamers, Nicole; Dani, Christian; Wabitsch, Martin; Berger, Ruud; Stunnenberg, Hendrik G; Mandrup, Susanne; Kalkhoven, Eric

    2009-09-25

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPARgamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPARgamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPARgamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPARgamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR:retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPARgamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.

  8. Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

    SciTech Connect

    Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

    2011-07-01

    Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

  9. Dose-independent pharmacokinetics of a new peroxisome proliferator-activated receptor-γ agonist, KR-62980, in Sprague-Dawley rats and ICR mice.

    PubMed

    Park, Jong-Shik; Kim, Min-Sun; Song, Jin Sook; Choi, Sung Heum; Lee, Byung Hoi; Woo, Jaechun; Ahn, Jin Hee; Bae, Myung Ae; Ahn, Sung-Hoon

    2011-12-01

    The pharmacokinetics of a novel peroxisome proliferator-activated receptor-γ agonist, KR-62980, were characterized in vitro with respect to liver metabolic stability, cell permeability, and plasma protein binding and in vivo using Sprague-Dawley rats and ICR mice. The metabolic half-life of 0.1-10 μM KR-62980 was 11.5-15.2 min in rat liver microsomes and 25.8-28.8 min in human liver microsomes. KR-62980 showed high permeability across MDCK cell monolayers, with apparent permeability coefficients of 20.4 × 10(-6) to 30.8 × 10(-6) cm/sec. The plasma protein binding rate of KR-62980 was 89.4%, and most was bound to serum albumin. After intravenous administration of KR-62980 (2 mg/kg), the systemic clearance was 2.50 L/h/kg, and the volume of distribution at steady-state was 9.16 L/kg. The bioavailability after oral administration was approximately 60.9%. The dose-normalized AUC values were 0.50 ± 0.09, 0.41 ± 0.20, and 0.62 ± 0.08 h · μg/mL after oral administration of 2, 5, and 10 mg/kg KR-62980, respectively, showing no dose-dependency. The in vivo pharmacokinetic parameters in ICR mice were also dose independent. These data suggest that KR-62980 is not significantly dose dependent in rats or mice, although it may disappear rapidly from the systemic circulation via metabolism in the liver.

  10. MicroRNA-128 inhibition attenuates myocardial ischemia/reperfusion injury-induced cardiomyocyte apoptosis by the targeted activation of peroxisome proliferator-activated receptor gamma

    PubMed Central

    ZENG, XIAO CONG; LI, LANG; WEN, HONG; BI, QI

    2016-01-01

    The aim of the present study was to investigate the effects of microRNA (miR)-128 inhibition on the targeted activation of peroxisome proliferator-activated receptor gamma (PPARG) and on cardiomyocyte apoptosis induced by myocardial ischemia/reperfusion (I/R) injury. In vitro, the expression of PPARG was detected by reverse transcription-quantitative polymerase chain reaction and western blotting in neonatal rat ventricular myocytes (NRVMs) and HEK293 cells transfected with the mimics or inhibitors of miR-128 or control RNA. Luciferase reporter assays were used to identify whether PPARG is a direct target of miR-128. In vivo, miR-128 was knocked down via ear vein injection of antagomir-128 in a rabbit myocardial I/R injury model. Western blotting investigated the activation of Akt [phosphorylated (p)-Akt] and the expression of total-Akt, PPARG and myeloid leukemia cell differentiation protein-1 (Mcl-1) in the myocardium. Cardiomyocyte apoptosis was examined with transmission electron microscropy and terminal deoxynucleotidyl transferase dUTP nick end labeling staining. PPARG mRNA and protein were downregulated in NRVMs transfected with miR-128 mimics, but upregulated by antagomir-128 compared with control. This indicates that PPARG is a direct miR-128 target. Activation of Akt (p-Akt), Mcl-1 and PPARG expression in the myocardium were increased by miR-128 inhibition. Furthermore, miR-128 antagomirs significantly reduced apoptosis in hearts subjected to I/R injury, which was blocked by the PPARG inhibitor GW9662. In conclusion, miR-128 inhibition attenuated I/R injury-induced cardiomyocyte apoptosis by the targeted activation of PPARG signaling. PMID:27150726

  11. Identification of 6-octadecynoic acid from a methanol extract of Marrubium vulgare L. as a peroxisome proliferator-activated receptor γ agonist

    SciTech Connect

    Ohtera, Anna; Miyamae, Yusaku; Nakai, Naomi; Kawachi, Atsushi; Kawada, Kiyokazu; Han, Junkyu; Isoda, Hiroko; Neffati, Mohamed; Akita, Toru; Maejima, Kazuhiro; Masuda, Seiji; Kambe, Taiho; Mori, Naoki; Irie, Kazuhiro; Nagao, Masaya

    2013-10-18

    Highlights: •6-ODA, a rare fatty acid with a triple bond, was identified from Marrubium vulgare. •6-ODA was synthesized from petroselinic acid as a starting material. •6-ODA stimulated lipid accumulation in HSC-T6 and 3T3-L1 cells. •The first report of a fatty acid with a triple bond functioning as a PPARγ agonist. •This study sheds light on novel functions of a fatty acid with a triple bond. -- Abstract: 6-Octadecynoic acid (6-ODA), a fatty acid with a triple bond, was identified in the methanol extract of Marrubium vulgare L. as an agonist of peroxisome proliferator-activated receptor γ (PPARγ). Fibrogenesis caused by hepatic stellate cells is inhibited by PPARγ whose ligands are clinically used for the treatment of diabetes. Plant extracts of Marrubium vulgare L., were screened for activity to inhibit fibrosis in the hepatic stellate cell line HSC-T6 using Oil Red-O staining, which detects lipids that typically accumulate in quiescent hepatic stellate cells. A methanol extract with activity to stimulate accumulation of lipids was obtained. This extract was found to have PPARγ agonist activity using a luciferase reporter assay. After purification using several chromatographic methods, 6-ODA, a fatty acid with a triple bond, was identified as a candidate of PPARγ agonist. Synthesized 6-ODA and its derivative 9-octadecynoic acid (9-ODA), which both have a triple bond but in different positions, activated PPARγ in a luciferase reporter assay and increased lipid accumulation in 3T3-L1 adipocytes in a PPARγ-dependent manner. There is little information about the biological activity of fatty acids with a triple bond, and to our knowledge, this is the first report that 6-ODA and 9-ODA function as PPARγ agonists.

  12. Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, Attenuates Inflammation Via NF-κB Inhibition in Lipopolysaccharide-Induced Peritonitis.

    PubMed

    Zhang, Yun-Fang; Zou, Xun-Liang; Wu, Jun; Yu, Xue-Qing; Yang, Xiao

    2015-12-01

    We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, in a lipopolysaccharide (LPS)-induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-κB-p65 and IκBα was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p-p65, and p-IκBα protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-κB-p65 and IκBα without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-κB phosphorylation, suggesting that NF-κB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-γ might be considered a potential therapeutic target against peritonitis.

  13. Peroxisome proliferator-activated receptor α activation attenuates the inflammatory response to protect the liver from acute failure by promoting the autophagy pathway.

    PubMed

    Jiao, M; Ren, F; Zhou, L; Zhang, X; Zhang, L; Wen, T; Wei, L; Wang, X; Shi, H; Bai, L; Zhang, X; Zheng, S; Zhang, J; Chen, Y; Han, Y; Zhao, C; Duan, Z

    2014-08-28

    Peroxisome proliferator-activated receptor α (PPARα) has been reported to induce a potent anti-inflammatory response. Autophagy is a recently recognized rudimentary cellular response to inflammation and injury. The aim of the present study was to test the hypothesis that PPARα activation mediates autophagy to inhibit liver inflammation and protect against acute liver failure (ALF). PPARα expression during ALF and the impact of PPARα activation by Wy-14 643 on the hepatic immune response were studied in a D-galactosamine/lipopolysaccharide-induced mouse model. Autophagy was inhibited by 3-methyladenine or small interfering RNA (siRNA) against Atg7. In both the mouse model and human ALF subjects, PPARα was significantly downregulated in the injured liver. PPARα activation by pretreatment with Wy-14 643 protected against liver injury in mice. The protective effect of PPARα activation relied on the suppression of inflammatory mechanisms through the induction of autophagy. This hypothesis is supported by the following evidence: first, PPARα activation suppressed proinflammatory responses and inhibited phosphorylated NF-κBp65, phosphorylated JNK and phosphorylated ERK pathways in vivo. Second, protection by PPARα activation was due to the induction of autophagy because inhibition of autophagy by 3-methyladenine or Atg7 siRNA reversed liver protection and inflammation. Third, PPARα activation directly induced autophagy in primary macrophages in vitro, which protected cells from a lipopolysaccharide-induced proinflammatory response. Here, for the first time, we have demonstrated that PPARα-mediated induction of autophagy ameliorated liver injury in cases of ALF by attenuating inflammatory responses, indicating a potential therapeutic application for ALF treatment.

  14. Proteomic characterization of peroxisome proliferator-activated receptor-γ (PPARγ) overexpressing or silenced colorectal cancer cells unveils a novel protein network associated with an aggressive phenotype.

    PubMed

    Milone, Maria Rita; Pucci, Biagio; Colangelo, Tommaso; Lombardi, Rita; Iannelli, Federica; Colantuoni, Vittorio; Sabatino, Lina; Budillon, Alfredo

    2016-10-01

    Peroxisome proliferator-activated receptor-γ (PPARγ) is a transcription factor of the nuclear hormone receptor superfamily implicated in a wide range of processes, including tumorigenesis. Its role in colorectal cancer (CRC) is still debated; most reports support that PPARγ reduced expression is associated with poor prognosis. We employed 2-Dimensional Differential InGel Electrophoresis (2-D DIGE) followed by Liquid Chromatography (LC)-tandem Mass Spectrometry (MS/MS) to identify differentially expressed proteins and the molecular pathways underlying PPARγ expression in CRC progression. We identified several differentially expressed proteins in HT29 and HCT116 CRC cells and derived clones either silenced or overexpressing PPARγ, respectively. In Ingenuity Pathway Analysis (IPA) they showed reciprocal relation with PPARγ and a strong relationship with networks linked to cell death, growth and survival. Interestingly, five of the identified proteins, ezrin (EZR), isoform C of prelamin-A/C (LMNA), alpha-enolase (ENOA), prohibitin (PHB) and RuvB-like 2 (RUVBL2) were shared by the two cell models with opposite expression levels, suggesting a possible regulation by PPARγ. mRNA and western blot analysis were undertaken to obtain a technical validation and confirm the expression trend observed by 2-D DIGE data. We associated EZR upregulation with increased cell surface localization in PPARγ-overexpressing cells by flow cytometry and immunofluorescence staining. We also correlated EZR and PPARγ expression in our series of CRC specimens and the expression profiling of all five proteins levels in the publicly available colon cancer genomic data from Oncomine and Cancer Genome Atlas (TCGA) colon adenocarcinoma (COAD) datasets. In summary, we identified a panel of proteins correlated with PPARγ expression that could be associated with CRC unveiling new pathways to be investigated for the selection of novel potential prognostic/predictive biomarkers and/or therapeutic

  15. The role of peroxisome proliferator-activated receptor-{beta}/{delta} in epidermal growth factor-induced HaCaT cell proliferation

    SciTech Connect

    Liang Pengfei; Jiang Bimei; Yang Xinghua; Xiao Xianzhong Huang Xu; Long Jianhong; Zhang Pihong; Zhang Minghua; Xiao Muzhang; Xie Tinghong; Huang Xiaoyuan

    2008-10-15

    Epidermal growth factor (EGF) has been shown to be a potent mitogen for epidermal cells both in vitro and in vivo, thus contributing to the development of an organism. It has recently become clear that peroxisome proliferator-activated receptor-{beta}/{delta} (PPAR{beta}/{delta}) expression and activation is involved in the cell proliferation. However, little is known about the role of PPAR{beta}/{delta} in EGF-induced proliferation of HaCaT keratinocytes. In this study, HaCaT cells were cultured in the presence and absence of EGF and we identified that EGF induced an increase of PPAR{beta}/{delta} mRNA and protein level expression in time-dependent and dose-dependent manner, and AG1487, an EGF receptor (EGFR) special inhibitor, caused attenuation of PPAR{beta}/{delta} protein expression. Electrophoretic mobility shift assay (EMSA) revealed that EGF significantly increased PPAR{beta}/{delta} binding activity in HaCaT keratinocytes. Antisense phosphorothioate oligonucleotides (asODNs) against PPAR{beta}/{delta} caused selectively inhibition of PPAR{beta}/{delta} protein content induced by EGF and significantly attenuated EGF-mediated cell proliferation. Treatment of the cells with L165041, a specific synthetic ligand for PPAR{beta}/{delta}, significantly enhanced EGF-mediated cell proliferation. Finally, c-Jun ablation inhibited PPAR{beta}/{delta} up-regulation induced by EGF, and chromatin immunoprecipitation (ChIP) showed that c-Jun bound to the PPAR{beta}/{delta} promoter and the binding increased in EGF-stimulated cells. These results demonstrate that EGF induces PPAR{beta}/{delta} expression in a c-Jun-dependent manner and PPAR{beta}/{delta} plays a vital role in EGF-stimulated proliferation of HaCaT cells.

  16. The peroxisome proliferator activated receptor gamma agonist pioglitazone increases functional expression of the glutamate transporter excitatory amino acid transporter 2 (EAAT2) in human glioblastoma cells

    PubMed Central

    Ching, Jared; Amiridis, Stephanie; Stylli, Stanley S.; Bjorksten, Andrew R.; Kountouri, Nicole; Zheng, Thomas; Paradiso, Lucy; Luwor, Rodney B.; Morokoff, Andrew P.; O'Brien, Terence J.; Kaye, Andrew H.

    2015-01-01

    Glioma cells release glutamate through expression of system xc−, which exchanges intracellular glutamate for extracellular cysteine. Lack of the excitatory amino acid transporter 2 (EAAT2) expression maintains high extracellular glutamate levels in the glioma microenvironment, causing excitotoxicity to surrounding parenchyma. Not only does this contribute to the survival and proliferation of glioma cells, but is involved in the pathophysiology of tumour-associated epilepsy (TAE). We investigated the role of the peroxisome proliferator activated receptor gamma (PPARγ) agonist pioglitazone in modulating EAAT2 expression in glioma cells. We found that EAAT2 expression was increased in a dose dependent manner in both U87MG and U251MG glioma cells. Extracellular glutamate levels were reduced with the addition of pioglitazone, where statistical significance was reached in both U87MG and U251MG cells at a concentration of ≥ 30 μM pioglitazone (p < 0.05). The PPARγ antagonist GW9662 inhibited the effect of pioglitazone on extracellular glutamate levels, indicating PPARγ dependence. In addition, pioglitazone significantly reduced cell viability of U87MG and U251MG cells at ≥ 30 μM and 100 μM (p < 0.05) respectively. GW9662 also significantly reduced viability of U87MG and U251MG cells with 10 μM and 30 μM (p < 0.05) respectively. The effect on viability was partially dependent on PPARγ activation in U87MG cells but not U251MG cells, whereby PPARγ blockade with GW9662 had a synergistic effect. We conclude that PPARγ agonists may be therapeutically beneficial in the treatment of gliomas and furthermore suggest a novel role for these agents in the treatment of tumour associated seizures through the reduction in extracellular glutamate. PMID:26046374

  17. Effects of CP-900691, a novel peroxisome proliferator-activated receptor α, agonist on diabetic nephropathy in the BTBR ob/ob mouse.

    PubMed

    Askari, Bardia; Wietecha, Tomasz; Hudkins, Kelly L; Fox, Edward J; O'Brien, Kevin D; Kim, Jinkyu; Nguyen, Tri Q; Alpers, Charles E

    2014-08-01

    Piperidine-based peroxisome proliferator-activated receptor-α agonists are agents that are efficacious in improving lipid, glycemic, and inflammatory indicators in diabetes and obesity. This study sought to determine whether CP-900691 ((S)-3-[3-(1-carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester; CP), a member of this novel class of agents, by decreasing plasma triglycerides, could prevent diabetic nephropathy in the Black and Tan, BRachyuric (BTBR) ob/ob mouse model of type 2 diabetes mellitus. Four-week old female BTBR WT and BTBR ob/ob mice received either regular chow or one containing CP (3 mg/kg per day) for 14 weeks. CP elevated plasma high-density lipoprotein, albuminuria, and urinary excretion of 8-epi PGF(2α), a product of the nonenzymatic metabolism of arachidonic acid and whose production is elevated in oxidative stress, in BTBR WT mice. In BTBR ob/ob mice, CP reduced plasma triglycerides and non-esterified fatty acids, fasting blood glucose, body weight, and plasma interleukin-6, while concomitantly improving insulin resistance. Despite these beneficial metabolic effects, CP had no effect on elevated plasma insulin, 8-epi PGF(2α) excretion, and albuminuria, and surprisingly, did not ameliorate the development of diabetic nephropathy, having no effect on the accumulation of renal macrophages, glomerular hypertrophy, and increased mesangial matrix expansion. In addition, CP did not increase plasma high-density lipoprotein in BTBR ob/ob mice, while paradoxically increasing total cholesterol levels. These findings indicate that 8-epi PGF(2α), possibly along with hyperinsulinemia and inflammatory and dysfunctional lipoproteins, is integral to the development of diabetic nephropathy and should be considered as a potential target of therapy in the treatment of diabetic nephropathy.

  18. Characterization of Peroxisome Proliferator-Activated Receptor a (PPARa) -Independent Effects of PPARa Activators in the Rodent Liver: Di-(2-ethylhexyl) phthalate Also Activates the Constitutive Activated Receptor

    EPA Science Inventory

    Peroxisome proliferator chemicals (PPC) are thought to mediate their effects in rodents on hepatocyte growth and liver cancer through the nuclear receptor peroxisome proliferatoractivated receptor alpha (PPARa). Recent studies indicate that one such PPC, the plasticizer di2- et...

  19. Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy

    SciTech Connect

    Hirano, Ken-ichi; Tanaka, Tatsuya; Ikeda, Yoshihiko; Yamaguchi, Satoshi; Zaima, Nobuhiro; Kobayashi, Kazuhiro; Sakata, Yasuhiko; and others

    2014-01-10

    Highlights: •Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare severe heart disease. •PPARγ is up-regulated in myocardium in patients with TGCV. •Possible vicious cycle for fatty acid may be involved in pathophysiology of TGCV. -- Abstract: Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, “Triglyceride deposit cardiomyovasculopathy (TGCV)”. Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5′ splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules’ lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients’ passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG

  20. MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells

    PubMed Central

    GU, JIAN-JUN; ZHANG, JIAN-HE; CHEN, HONG-JIE; WANG, SHOU-SEN

    2016-01-01

    MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non-neoplastic brain specimens. Specifically, higher expression levels of miR-130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR-130b interacted with the 3′-untranslated region of peroxisome proliferator-activated receptor-γ (PPAR-γ), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR-130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR-130b in U251 glioma cells restored the expression of PPAR-γ and E-cadherin, and inhibited the expression of β-catenin. Notably, PPAR-γ knockdown abolished the inhibitory effect of miR-130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR-130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-γ. PMID:27122306

  1. Cell death is induced by ciglitazone, a peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) agonist, independently of PPAR{gamma} in human glioma cells

    SciTech Connect

    Lee, Myoung Woo; Kim, Dae Seong; Kim, Hye Ryung; Kim, Hye Jin; Yang, Jin Mo; Ryu, Somi; Noh, Yoo Hun; Lee, Soo Hyun; Son, Meong Hi; Jung, Hye Lim; Yoo, Keon Hee; Koo, Hong Hoe; Sung, Ki Woong

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Greater than 30 {mu}M ciglitazone induces cell death in glioma cells. Black-Right-Pointing-Pointer Cell death by ciglitazone is independent of PPAR{gamma} in glioma cells. Black-Right-Pointing-Pointer CGZ induces cell death by the loss of MMP via decreased Akt. -- Abstract: Peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) regulates multiple signaling pathways, and its agonists induce apoptosis in various cancer cells. However, their role in cell death is unclear. In this study, the relationship between ciglitazone (CGZ) and PPAR{gamma} in CGZ-induced cell death was examined. At concentrations of greater than 30 {mu}M, CGZ, a synthetic PPAR{gamma} agonist, activated caspase-3 and induced apoptosis in T98G cells. Treatment of T98G cells with less than 30 {mu}M CGZ effectively induced cell death after pretreatment with 30 {mu}M of the PPAR{gamma} antagonist GW9662, although GW9662 alone did not induce cell death. This cell death was also observed when cells were co-treated with CGZ and GW9662, but was not observed when cells were treated with CGZ prior to GW9662. In cells in which PPAR{gamma} was down-regulated cells by siRNA, lower concentrations of CGZ (<30 {mu}M) were sufficient to induce cell death, although higher concentrations of CGZ ( Greater-Than-Or-Slanted-Equal-To 30 {mu}M) were required to induce cell death in control T98G cells, indicating that CGZ effectively induces cell death in T98G cells independently of PPAR{gamma}. Treatment with GW9662 followed by CGZ resulted in a down-regulation of Akt activity and the loss of mitochondrial membrane potential (MMP), which was accompanied by a decrease in Bcl-2 expression and an increase in Bid cleavage. These data suggest that CGZ is capable of inducing apoptotic cell death independently of PPAR{gamma} in glioma cells, by down-regulating Akt activity and inducing MMP collapse.

  2. Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

    SciTech Connect

    Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro; Yasuda, Osamu; Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei; Ogawa, Hisao; Kim-Mitsuyama, Shokei

    2011-07-08

    Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of

  3. Bezafibrate, a peroxisome proliferator-activated receptor α agonist, decreases circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes.

    PubMed

    Terasawa, Tomoko; Aso, Yoshimasa; Omori, Kyoko; Fukushima, Maiko; Momobayashi, Atsushi; Inukai, Toshihiko

    2015-02-01

    CD14(+)CD16(+) monocytes are proinflammatory cells that produce tumor necrosis factor and interleukin (IL)-1β. The number of circulating CD14(+)CD16(+) monocytes is increased in patients with chronic renal failure or coronary artery disease. We investigated the effect of bezafibrate, a peroxisome proliferator-activated receptor α agonist, on circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes. Using cells isolated from type 2 diabetic subjects, we also examined the in vitro expression of CD16 messenger RNA (mRNA) by mononuclear cells (MNCs) exposed to bezafibrate. The percentage of CD14(+)CD16(+) monocytes among all CD14(+) monocytes was significantly higher in subjects with impaired glucose tolerance (P < 0.01) or type 2 diabetes (P < 0.05) than in those with normal glucose tolerance. The percentage of CD14(+)CD16(+) monocytes was significantly lower in patients with type 2 diabetes who were taking bezafibrate (400 mg/d) than in patients not taking it (P < 0.01). Treatment with bezafibrate for 12 weeks significantly reduced the percentage of circulating CD14(+)CD16(+) monocytes from 45.4 ± 25.2% to 38.3 ± 21.8% (P = 0.0144). In an in vitro study, the expression of CD16 mRNA by MNCs from 6 diabetic subjects was decreased after 24 hours of treatment with 10 μg/mL of bezafibrate (P < 0.05). Expression of IL-1β mRNA by MNCs was also decreased after 24 hours of treatment with 10 μg/mL of bezafibrate, whereas the IL-1β level in the culture supernatant was significantly decreased after treatment of MNCs with either 1 or 10 μg/mL of bezafibrate. In conclusion, bezafibrate decreased circulating CD14(+)CD16(+) monocytes in patients with type 2 diabetes, probably by inhibiting the expression of CD16 mRNA. PMID:25134759

  4. Smooth Muscle Peroxisome Proliferator-Activated Receptor γ Plays a Critical Role in Formation and Rupture of Cerebral Aneurysms in Mice In Vivo.

    PubMed

    Hasan, David M; Starke, Robert M; Gu, He; Wilson, Katina; Chu, Yi; Chalouhi, Nohra; Heistad, Donald D; Faraci, Frank M; Sigmund, Curt D

    2015-07-01

    Vascular inflammation plays a critical role in the pathogenesis of cerebral aneurysms. Peroxisome proliferator-activated receptor γ (PPARγ) protects against vascular inflammation and atherosclerosis, whereas dominant-negative mutations in PPARγ promote atherosclerosis and vascular dysfunction. We tested the role of PPARγ in aneurysm formation and rupture. Aneurysms were induced with a combination of systemic infusion of angiotensin-II and local injection of elastase in (1) mice that received the PPARγ antagonist GW9662 or the PPARγ agonist pioglitazone, (2) mice carrying dominant-negative PPARγ mutations in endothelial or smooth muscle cells, and (3) mice that received the Cullin inhibitor MLN4924. Incidence of aneurysm formation, rupture, and mortality was quantified. Cerebral arteries were analyzed for expression of Cullin3, Kelch-like ECH-associated protein 1, nuclear factor (erythroid-derived 2)-like 2, NAD(P)H dehydrogenase (quinone)1 (NQO1), and inflammatory marker mRNAs. Neither pioglitazone nor GW9662 altered the incidence of aneurysm formation. GW9662 significantly increased the incidence of aneurysm rupture, whereas pioglitazone tended to decrease the incidence of rupture. Dominant-negative endothelial-specific PPARγ did not alter the incidence of aneurysm formation or rupture. In contrast, dominant-negative smooth muscle-specific PPARγ resulted in an increase in aneurysm formation (P<0.05) and rupture (P=0.05). Dominant-negative smooth muscle-specific PPARγ, but not dominant-negative endothelial-specific PPARγ, resulted in significant decreases in expression of genes encoding Cullin3, Kelch-like ECH-associated protein 1, and nuclear factor (erythroid-derived 2)-like 2, along with significant increases in tumor necrosis factor-α, monocyte chemoattractant protein-1, chemokine (C-X-C motif) ligand 1, CD68, matrix metalloproteinase-3, -9, and -13. MLN4924 did not alter incidence of aneurysm formation, but increased the incidence of rupture (P<0

  5. Peroxisome proliferator-activated receptor-α-mediated transcription of miR-199a2 attenuates endothelin-1 expression via hypoxia-inducible factor-1α.

    PubMed

    Li, Chen; Mpollo, Marthe-Sandrine Eiymo Mwa; Gonsalves, Caryn S; Tahara, Stanley M; Malik, Punam; Kalra, Vijay K

    2014-12-26

    Endothelin-1, a potent vasoconstrictor, plays an important role in pulmonary hypertension (PH) in sickle cell disease (SCD). Our previous studies show that higher levels of placenta growth factor (PlGF), secreted by erythroid precursor cells, correlate with increased plasma levels of endothelin-1 (ET-1) and other functional markers of PH in SCD. PlGF-mediated ET-1 expression occurs via activation of hypoxia-inducible factor-1α (HIF-1α). However, relatively less is understood regarding how PlGF-mediated expression of HIF-1α and its downstream effector ET-1 are post-transcriptionally regulated. Herein, we show that PlGF treatment of endothelial cells resulted in reduced levels of miR-199a2, which targeted the 3'-UTR of HIF-1α mRNA and concomitantly led to augmented ET-1 expression. Plasma levels of miR-199a2 in SCD subjects were significantly lower with reciprocally high levels of plasma ET-1, unlike unaffected controls. This observation provided a molecular link between miR-199a2 and high levels of ET-1 in SCD. Furthermore, we show that miR-199a2 located in the DNM3os transcription unit was co-transcriptionally regulated by peroxisome proliferator-activated receptor α (PPARα). Binding of the latter to PPARα cis-elements in the promoter of DNM3os was demonstrated by promoter mutational analysis and ChIP. Additionally, we show that fenofibrate, a PPARα agonist, increased the expression of miR-199a2 and DNM3os; the former was responsible for reduced expression of HIF-1α and ET-1. In vivo studies of fenofibrate-fed Berkeley sickle mice resulted in increased levels of miR-199a2 and reduced levels of ET-1 in lung tissues. Our studies provide a potential therapeutic approach whereby fenofibrate-induced miR-199a2 expression can ameliorate PH by reduction of ET-1 levels.

  6. Vascular and Central Activation of Peroxisome Proliferator-Activated Receptor-β Attenuates Angiotensin II-Induced Hypertension: Role of RGS-5.

    PubMed

    Romero, Miguel; Jiménez, Rosario; Toral, Marta; León-Gómez, Elvira; Gómez-Gúzman, Manuel; Sánchez, Manuel; Zarzuelo, María José; Rodríguez-Gómez, Isabel; Rath, Geraldine; Tamargo, Juan; Pérez-Vizcaíno, Francisco; Dessy, Chantal; Duarte, Juan

    2016-07-01

    Activation of peroxisome proliferator-activated receptor-β/δ (PPARβ) lowers blood pressure in genetic and mineralocorticoid-induced hypertension. Regulator of G-protein-coupled receptor signaling 5 (RGS5) protein, which interferes in angiotensin II (AngII) signaling, is a target gene to PPARβ The aim of the present study was to examine whether PPARβ activation in resistance arteries and brain tissues prevents the elevated blood pressure in AngII-induced hypertension and evaluate the role of RGS5 in this effect. C57BL/6J male mice were divided into five groups (control mice, PPARβ agonist [4-[[[2-[3-Fluoro-4-(trifluoromethyl)phenyl]-4-methyl-5-thiazolyl]methyl]thio]-2-methylphenoxy]acetic acid (GW0742)-treated mice AngII-infused mice, GW0742-treated AngII-infused mice, and AngII-infused mice treated with GW0742 plus PPARβ antagonist 3-[[[2-Methoxy-4-(phenylamino)phenyl]amino]sulfonyl]-2-thiophenecarboxylic acid methyl ester (GSK0660)) and were followed for 3 weeks. GW0742 prevented the increase in both arterial blood pressure and plasma noradrenaline levels and the higher reduction of blood pressure after ganglionic blockade, whereas it reduced the mesenteric arterial remodeling and the hyper-responsiveness to vasoconstrictors (AngII and endothelin-1) in AngII-infused mice. These effects were accompanied by an inhibition of NADPH oxidase expression and activity in the brain. Gene expression profiling revealed a marked loss of brainstem and vascular RGS5 in AngII-infused mice, which was restored by GW0742. GW0742-induced effects were abolished by GSK0660. Small interfering RNA targeting RGS5 caused augmented contractile response to AngII in resistance mesenteric arteries and blunted the inhibitory effect of GW0742 on this response. In conclusion, GW0742 exerted antihypertensive effects, restoring sympathetic tone and vascular structure and function in AngII-infused mice by PPARβ activation in brain and vessels inhibiting AngII signaling as a result of RGS5

  7. Peroxisome proliferator-activated receptors α and γ are linked with alcohol consumption in mice and withdrawal and dependence in humans

    PubMed Central

    Blednov, Yuri A.; Benavidez, Jillian M.; Black, Mendy; Ferguson, Laura B.; Schoenhard, Grant L.; Goate, Alison M.; Edenberg, Howard J.; Wetherill, Leah; Hesselbrock, Victor; Foroud, Tatiana; Harris, R. Adron

    2014-01-01

    Background Peroxisome proliferator-activated receptor (PPAR) agonists reduce voluntary ethanol consumption in rat models and are promising therapeutics in the treatment of drug addictions. We studied the effects of different classes of PPAR agonists on chronic ethanol intake and preference in mice with a genetic predisposition for high alcohol consumption and then examined human genome wide association data for polymorphisms in PPAR genes in alcohol-dependent subjects. Methods Two different behavioral tests were used to measure intake of 15% ethanol in C57BL/6J male mice: 24-hour two-bottle choice and limited access (3-hour) two-bottle choice, drinking in the dark. We measured the effects of pioglitazone (10 and 30 mg/kg), fenofibrate (50 and 150 mg/kg), GW0742 (10 mg/kg), tesaglitazar (1.5 mg/kg) and bezafibrate (25 and 75 mg/kg) on ethanol intake and preference. Fenofibric acid, the active metabolite of fenofibrate, was quantified in mouse plasma, liver, and brain by LC-MS/MS. Data from a human genome wide association study (GWAS) completed in the Collaborative Study on the Genetics of Alcoholism (COGA) was then used to analyze the association of single nucleotide polymorphisms (SNPs) in different PPAR genes (PPARA, PPARD, PPARG, and PPARGC1A) with two phenotypes: DSM-IV alcohol dependence (AD) and the DSM-IV criterion of withdrawal. Results Activation of two isoforms of PPARs, α and γ, reduced ethanol intake and preference in the two different consumption tests in mice. However, a selective PPARδ agonist or a pan agonist for all three PPAR isoforms did not decrease ethanol consumption. Fenofibric acid, the active metabolite of the PPARα agonist fenofibrate, was detected in liver, plasma, and brain after 1 or 8 days of oral treatment. The GWAS from COGA supported an association of SNPs in PPARA and PPARG with alcohol withdrawal and PPARGC1A with AD but found no association for PPARD with either phenotype. Conclusions We provide convergent evidence using both

  8. Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.

    PubMed Central

    Kok, Tineke; Bloks, Vincent W; Wolters, Henk; Havinga, Rick; Jansen, Peter L M; Staels, Bart; Kuipers, Folkert

    2003-01-01

    Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 ( Mdr2 ), encoding the canalicular phospholipid translocator. The physiological role of PPARalpha in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a / 1b, Abca1 and Abcg5 / Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na(+)-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide 1 gene) or in bile formation between wild-type and Ppar alpha((-/-)) mice. Upon treatment of wild-type mice with ciprofibrate (0.05%, w/w, in diet for 2 weeks), the expression of Mdr2 (+3-fold), Mdr1a (+6-fold) and Mdr1b (+11-fold) mRNAs was clearly induced, while that of Oatp1 (-5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wild-type mouse hepatocytes to PPARalpha agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a / 1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a approximately 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Ppar alpha((-/-)) mice. In conclusion, our results show that basal bile formation is not affected by PPARalpha deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARalpha, while the induction of Mdr1a / 1b in vivo probably reflects a secondary phenomenon related to chronic PPARalpha activation. PMID:12381268

  9. MiR-132 regulates osteogenic differentiation via downregulating Sirtuin1 in a peroxisome proliferator-activated receptor β/δ-dependent manner.

    PubMed

    Gong, Kai; Qu, Bo; Liao, Dongfa; Liu, Da; Wang, Cairu; Zhou, Jingsong; Pan, Xianming

    2016-09-01

    MicroRNAs (miRNAs) play significant roles in multiple diseases by regulating the expression of their target genes. Type 2 diabetes mellitus (T2DM) is a chronic endocrine and metabolic disease with complex mechanisms. T2DM can result in diabetic osteoporosis (DO), which is characterized by bone loss, decreased bone mineral density and increased bone fractures. The promotion of osteogenic differentiation of osteoblasts is an effective way to treat osteoporosis. In the present study, high glucose (HG) and free fatty acids (FFA) were employed to mimic T2DM in MC3T3-E1 cells. To induce osteogenic differentiation, MC3T3-E1 cells were cultured in osteogenic medium. The results showed that osteogenic differentiation was significantly suppressed by HG and FFA. We found that miR-132 expression was significantly upregulated and much higher in HG-FFA-induced cells than other selected miRNAs, indicating that miR-132 might play an important role in DO. Furthermore, overexpression of miR-132 markedly inhibited the expression of key markers of osteogenic differentiation and alkaline phosphatase (ALP) activity. Reciprocally, inhibition of miR-132 restored osteogenic differentiation, even under treatment with HG-FFA. We also showed that Sirtuin 1 (Sirt1) was one of the target genes of miR-132, whose expression was controlled by miR-132. Ectopic expression of Sirt1 reversed the decrease in osteogenic differentiation caused by miR-132 and HG-FFA. These results demonstrated the direct role of miR-132 in suppressing osteogenic differentiation through downregulating Sirt1. Moreover, we demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) was a downstream molecule of Sirt1, and its knockout by PPARβ/δ siRNA significantly abolished the promotive effects of Sirt1 on osteogenic differentiation, indicating that Sirt1 functioned in a PPARβ/δ-dependent manner. Taken together, we provide crucial evidence that miR-132 plays a key role in regulating osteogenic

  10. Peroxisome proliferator-activated receptor delta +294T > C polymorphism and serum lipid levels in the Guangxi Bai Ku Yao and Han populations

    PubMed Central

    2010-01-01

    Background The association of peroxisome proliferator-activated receptor delta (PPARD) +294T > C polymorphism and serum lipid levels is inconsistent in several previous studies. Bai Ku Yao is an isolated subgroup of the Yao minority in China. The present study was undertaken to detect the association of PPARD +294T > C (rs2016520) polymorphism and several environmental factors with serum lipid levels in the Guangxi Bai Ku Yao and Han populations. Methods A total of 609 subjects of Bai Ku Yao and 573 participants of Han Chinese were randomly selected from our previous stratified randomized cluster samples. Genotyping of the PPARD +294T > C polymorphism was performed by polymerase chain reaction and restriction fragment length polymorphism combined with gel electrophoresis, and then confirmed by direct sequencing. Results The levels of serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), apolipoprotein (Apo) AI and ApoB were lower in Bai Ku Yao than in Han (P < 0.001 for all). The frequency of T and C alleles was 77.50% and 22.50% in Bai Ku Yao, and 72.43% and 27.57% in Han (P < 0.01); respectively. The frequency of TT, TC and CC genotypes was 60.59%, 33.83% and 5.53% in Bai Ku Yao, and 52.18%, 40.50% and 7.32% in Han (P < 0.05); respectively. The subjects with CC genotype in Bai Ku Yao had higher serum LDL-C and ApoB levels and lower the ratio of ApoAI to ApoB than the subjects with TT and TC genotypes in females but not in males. The C allele carriers in Han had higher serum TC levels in males (P < 0.01) and ApoB levels in females (P < 0.05) than the C allele noncarriers. Serum TC and ApoB levels were correlated with genotypes in Han (P < 0.05 for each) but not in Bai Ku Yao. Serum lipid parameters were also correlated with sex, age, body mass index, alcohol consumption, cigarette smoking, and blood pressure in both ethnic groups. Conclusions These results suggest that the association of PPARD +294T > C polymorphism and serum lipid levels is

  11. Activation of peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

    SciTech Connect

    Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

    2011-06-24

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. {yields} PPAR{alpha} activation also increased oxygen consumption rate and CO{sub 2} production and decreased secretion of triglyceride and ApoB from Caco-2 cells. {yields} Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO{sub 2} production in small intestinal epithelial cells. {yields} Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. {yields} It suggested that intestinal lipid metabolism regulated by PPAR{alpha} activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-{alpha} which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPAR{alpha} activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPAR{alpha} activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPAR{alpha} agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and

  12. In vivo and ex vivo regulation of breast cancer resistant protein (Bcrp) by peroxisome proliferator-activated receptor alpha (Pparα) at the blood-brain barrier.

    PubMed

    Hoque, Md Tozammel; Shah, Arpit; More, Vijay; Miller, David S; Bendayan, Reina

    2015-12-01

    Breast cancer resistance protein (Bcrp/Abcg2) localized at the blood-brain barrier (BBB) limits permeability into the brain of many xenobiotics, including pharmacological agents. Peroxisome proliferator-activated receptor α (Pparα), a ligand-activated transcription factor, primarily involved in lipid metabolism, has been shown to regulate the functional expression of Bcrp in human cerebral microvascular endothelial cells (hCMEC/D3). The aim of this study was to investigate ex vivo and in vivo, the regulation of Bcrp by Pparα in an intact BBB. Ex vivo quantitative real-time PCR and immunoblot analyses showed significant up-regulation of Abcg2/Bcrp mRNA and protein levels in CD-1 mouse brain capillaries incubated with clofibrate, a Pparα ligand. Fluorescence-based transport assays in CD-1 and C57BL/6 brain capillaries showed that exposure to clofibrate significantly increased Bcrp transport activity. This increase was not observed in capillaries isolated from Pparα knockout mice. In vivo, we found: i) significant Bcrp protein up-regulation in clofibrate-dosed CD-1 and C57BL/6 capillary lysates, but no effect in Pparα knockout capillary lysates, and ii) significantly increased Bcrp transport activity in capillaries isolated from clofibrate-treated mice. These results demonstrate an increase in Bcrp functional expression by Pparα in brain capillaries, and suggest that Pparα is another nuclear receptor that can contribute to the regulation of membrane efflux transporters and drug permeability at the BBB. We propose the involvement of the following pathways in clofibrate-mediated induction of the drug transporter Abcg2/Bcrp mRNA, protein expression and function by the nuclear receptor Pparα, in mouse brain capillary endothelial cells. Upon activation with clofibrate (Pparα, ligand), Pparα complex translocates from the cytoplasm into the nucleus and further recruits coactivators and transcription machinery which induce the transcription of Abcg2 gene and

  13. MiR-132 regulates osteogenic differentiation via downregulating Sirtuin1 in a peroxisome proliferator-activated receptor β/δ-dependent manner.

    PubMed

    Gong, Kai; Qu, Bo; Liao, Dongfa; Liu, Da; Wang, Cairu; Zhou, Jingsong; Pan, Xianming

    2016-09-01

    MicroRNAs (miRNAs) play significant roles in multiple diseases by regulating the expression of their target genes. Type 2 diabetes mellitus (T2DM) is a chronic endocrine and metabolic disease with complex mechanisms. T2DM can result in diabetic osteoporosis (DO), which is characterized by bone loss, decreased bone mineral density and increased bone fractures. The promotion of osteogenic differentiation of osteoblasts is an effective way to treat osteoporosis. In the present study, high glucose (HG) and free fatty acids (FFA) were employed to mimic T2DM in MC3T3-E1 cells. To induce osteogenic differentiation, MC3T3-E1 cells were cultured in osteogenic medium. The results showed that osteogenic differentiation was significantly suppressed by HG and FFA. We found that miR-132 expression was significantly upregulated and much higher in HG-FFA-induced cells than other selected miRNAs, indicating that miR-132 might play an important role in DO. Furthermore, overexpression of miR-132 markedly inhibited the expression of key markers of osteogenic differentiation and alkaline phosphatase (ALP) activity. Reciprocally, inhibition of miR-132 restored osteogenic differentiation, even under treatment with HG-FFA. We also showed that Sirtuin 1 (Sirt1) was one of the target genes of miR-132, whose expression was controlled by miR-132. Ectopic expression of Sirt1 reversed the decrease in osteogenic differentiation caused by miR-132 and HG-FFA. These results demonstrated the direct role of miR-132 in suppressing osteogenic differentiation through downregulating Sirt1. Moreover, we demonstrated that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) was a downstream molecule of Sirt1, and its knockout by PPARβ/δ siRNA significantly abolished the promotive effects of Sirt1 on osteogenic differentiation, indicating that Sirt1 functioned in a PPARβ/δ-dependent manner. Taken together, we provide crucial evidence that miR-132 plays a key role in regulating osteogenic

  14. Effects of the peroxisome proliferator-activated receptor-alpha agonists clofibrate and fish oil on hepatic fatty acid metabolism in weaned dairy calves.

    PubMed

    Litherland, N B; Bionaz, M; Wallace, R L; Loor, J J; Drackley, J K

    2010-06-01

    Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists increase fatty acid oxidation in liver of nonruminants. If similar effects occur in dairy cattle, enhanced hepatic oxidative capacity could decrease circulating nonesterified fatty acids and hepatic triacylglycerol accumulation in periparturient cows. The objectives of this study were 1) to determine whether partitioning of fatty acid metabolism by liver slices from weaned Holstein calves treated with PPARalpha agonists in vivo is altered compared with partitioning by liver slices from control (untreated) calves, and 2) to measure in vitro metabolism of palmitate and oleate by bovine liver slices and relate these to mRNA abundance for key enzymes. Weaned male Holstein calves (7 wk old; n=15) were assigned to 1 of 3 groups for a 5-d treatment period: control (untreated), clofibrate (62.5 mg/kg of BW), or fish oil (250 mg/kg of BW). Calves treated with clofibrate consumed less dry matter. Body weight, liver weight, liver weight:body weight ratio, blood nonesterified fatty acids, beta-hydroxybutyrate, and liver composition were not significantly different among treatments. Liver slices were incubated for 2, 4, and 8 h to determine in vitro conversion of [1-(14)C] palmitate and [1-(14)C] oleate to CO(2), acid-soluble products, esterified products, and total metabolism. In liver slices incubated for 8 h, conversion of palmitate to CO(2) was greater for calves treated with clofibrate compared with control calves or calves treated with fish oil. Conversion of palmitate to esterified products, total palmitate metabolism, and metabolism of oleate were not different among treatments. Conversion of palmitate to CO(2) was greater than that from oleate for all treatments, but rates of total metabolism did not differ. Clofibrate increased or tended to increase liver expression of several PPARalpha target genes involved in fatty acid oxidation (e.g., ACADVL, ACOX1, CPT1A), whereas fish oil did not significantly

  15. Carob pod insoluble fiber exerts anti-atherosclerotic effects in rabbits through sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α.

    PubMed

    Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Lahera, Vicente; de las Heras, Natalia

    2014-09-01

    The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ⋅ kg(-1) ⋅ d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ⋅ kg(-1) ⋅ d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-α (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-β (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of

  16. Carob pod insoluble fiber exerts anti-atherosclerotic effects in rabbits through sirtuin-1 and peroxisome proliferator-activated receptor-γ coactivator-1α.

    PubMed

    Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Lahera, Vicente; de las Heras, Natalia

    2014-09-01

    The aim of this study was to evaluate the potential effects of an insoluble dietary fiber from carob pod (IFC) (1 g ⋅ kg(-1) ⋅ d(-1) in the diet) on alterations associated with atherosclerosis in rabbits with dyslipidemia. Male New Zealand rabbits (n = 30) were fed the following diets for 8 wk: 1) a control diet (SF412; Panlab) as a control group representing normal conditions; 2) a control supplemented with 0.5% cholesterol + 14% coconut oil (DL) (SF302; Panlab) for 8 wk as a dyslipidemic group; and 3) a control containing 0.5% cholesterol + 14% coconut oil plus IFC (1 g ⋅ kg(-1) ⋅ d(-1)) (DL+IFC) for 8 wk. IFC was administered in a pellet mixed with the DL diet. The DL-fed group developed mixed dyslipidemia and atherosclerotic lesions, which were associated with endothelial dysfunction, inflammation, and fibrosis. Furthermore, sirtuin-1 (SIRT1) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein expression in the aorta were reduced to 77% and 63% of the control group, respectively (P < 0.05), in these rabbits. Administration of IFC to DL-fed rabbits reduced the size of the aortic lesion significantly (DL, 15.2% and DL+IFC, 2.6%) and normalized acetylcholine-induced relaxation (maximal response: control, 89.3%; DL, 61.6%; DL+IFC, 87.1%; P < 0.05) and endothelial nitric oxide synthase expression (DL, 52% and DL+IFC, 104% of the control group). IFC administration to DL-fed rabbits also reduced cluster of differentiation 36 (DL, 148% and DL+IFC, 104% of the control group; P < 0.05), plasminogen activator inhibitor-1 (DL, 141% and DL+IFC, 107% of the control group), tumor necrosis factor-α (DL, 166% and DL+IFC, 120% of the control group), vascular cell adhesion molecule-1 (DL, 153% and DL+IFC, 110% of the control group), transforming growth factor-β (DL, 173% and DL+IFC, 99% of the control group), and collagen I (DL, 157% and DL+IFC, 112% of the control group) in the aorta. These effects were accompanied by an enhancement of

  17. Impact of peroxisome proliferator-activated receptor γ on angiotensin II type 1 receptor-mediated insulin sensitivity, vascular inflammation and atherogenesis in hypercholesterolemic mice

    PubMed Central

    Becher, Ulrich M.; Camara, Bakary; Yildirimtürk, Cihan; Aksoy, Adem; Kebschull, Moritz; Werner, Nikos; Nickenig, Georg; Müller, Cornelius

    2015-01-01

    Introduction The angiotensin II type 1 receptor (AT1R) and the peroxisome proliferator-activated receptor γ (PPARγ) have been implicated in the pathogenesis of atherosclerosis. A number of studies have reported that AT1R inhibition or genetic AT1R disruption and PPARγ activation inhibit vascular inflammation and improve glucose and lipid metabolism, underscoring a molecular interaction of AT1R and PPARγ. We here analyzed the hypothesis that vasculoprotective anti-inflammatory and metabolic effects of AT1R inhibition are mediated by PPARγ. Material and methods Female ApoE–/–/AT1R–/– mice were fedwith a high-fat and cholesterol-rich diet and received continuous treatment with the selective PPARγ antagonist GW9662 or vehicle at a rate of 700 ng/kg/min for 4 weeks using subcutaneously implanted osmotic mini-pumps. Additionally, one group of female ApoE–/– mice served as a control group. After treatment for 4 weeks mice were sacrificed and read-outs (plaque development, vascular inflammation and insulinsensitivity) were performed. Results Using AT1R deficient ApoE–/– mice (ApoE–/–/AT1R–/– mice) we found decreased cholesterol-induced endothelial dysfunction and atherogenesis compared to ApoE–/– mice. Inhibition of PPARγ by application of the specific PPARγ antagonist GW9662 significantly abolished the anti-atherogenic effects of AT1R deficiency in ApoE–/–/AT1R–/– mice (plaque area as % of control: ApoE–/–: 39 ±5%; ApoE–/–/AT1R–/–: 17 ±7%, p = 0.044 vs. ApoE–/–; ApoE–/–/AT1R–/– + GW9662: 31 ±8%, p = 0.047 vs. ApoE–/–/AT1R–/–). Focusing on IL6 as a pro-inflammatory humoral marker we detected significantly increased IL-6 levels in GW9662-treated animals (IL-6 in pg/ml: ApoE–/–: 230 ±16; ApoE–/–/AT1R–/–: 117 ±20, p = 0.01 vs. ApoE–/–; ApoE–/–/AT1R–/– + GW9662: 199 ±20, p = 0.01 vs. ApoE–/–/AT1R–/–), while the anti-inflammatory marker IL-10 was significantly

  18. Hypoxia-inducible factor-1α in vascular smooth muscle regulates blood pressure homeostasis through a peroxisome proliferator-activated receptor-γ-angiotensin II receptor type 1 axis.

    PubMed

    Huang, Yan; Di Lorenzo, Annarita; Jiang, Weidong; Cantalupo, Anna; Sessa, William C; Giordano, Frank J

    2013-09-01

    Hypertension is a major worldwide health issue for which only a small proportion of cases have a known mechanistic pathogenesis. Of the defined causes, none have been directly linked to heightened vasoconstrictor responsiveness, despite the fact that vasomotor tone in resistance vessels is a fundamental determinant of blood pressure. Here, we reported a previously undescribed role for smooth muscle hypoxia-inducible factor-1α (HIF-1α) in controlling blood pressure homeostasis. The lack of HIF-1α in smooth muscle caused hypertension in vivo and hyperresponsiveness of resistance vessels to angiotensin II stimulation ex vivo. These data correlated with an increased expression of angiotensin II receptor type I in the vasculature. Specifically, we show that HIF-1α, through peroxisome proliferator-activated receptor-γ, reciprocally defined angiotensin II receptor type I levels in the vessel wall. Indeed, pharmacological blockade of angiotensin II receptor type I by telmisartan abolished the hypertensive phenotype in smooth muscle cell-HIF-1α-KO mice. These data revealed a determinant role of a smooth muscle HIF-1α/peroxisome proliferator-activated receptor-γ/angiotensin II receptor type I axis in controlling vasomotor responsiveness and highlighted an important pathway, the alterations of which may be critical in a variety of hypertensive-based clinical settings. PMID:23918749

  19. Chimeric mice with hepatocyte-humanized liver as an appropriate model to study human peroxisome proliferator-activated receptor-α.

    PubMed

    Tateno, Chise; Yamamoto, Toshinobu; Utoh, Rie; Yamasaki, Chihiro; Ishida, Yuji; Myoken, Yuka; Oofusa, Ken; Okada, Miyoko; Tsutsui, Naohisa; Yoshizato, Katsutoshi

    2015-02-01

    Peroxisome proliferator (PP)-activated receptor-α (PPARα) agonists exhibit species-specific effects on livers of the rodent and human (h), which has been considered to reside in the difference of PPARα gene structures. However, the contribution of h-hepatocytes (heps) to the species-specificity remains to be clarified. In this study, the effects of fenofibrate were investigated using a hepatocyte-humanized chimeric mouse (m) model whose livers were replaced with h-heps at >70%. Fenofibrate induced hepatocellular hypertrophy, cell proliferation, and peroxisome proliferation in livers of severe combined immunodeficiency (SCID) mice, but not in the h-hep of chimeric mouse livers. Fenofibrate increased the expression of the enzymes of β- and ω-hydroxylation and deoxygenation of lipids at both gene and protein levels in SCID mouse livers, but not in the h-heps of chimeric mouse livers, supporting the studies with h-PPARα-transgenic mice, a hitherto reliable model for studying the regulation of h-PPARα in the h-liver in most respects, except the induction of the peroxisome proliferation. This study indicates the importance of not only h-PPARα gene but also h-heps themselves to correctly predict effects of fibrates on h-livers, and, therefore, suggests that the chimeric mouse is a currently available, consistent, and reliable model to obtain pharmaceutical data concerning the effects of fibrates on h-livers.

  20. Phytol directly activates peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) and regulates gene expression involved in lipid metabolism in PPAR{alpha}-expressing HepG2 hepatocytes

    SciTech Connect

    Goto, Tsuyoshi; Takahashi, Nobuyuki; Kato, Sota; Egawa, Kahori; Ebisu, Shogo; Moriyama, Tatsuya; Fushiki, Tohru; Kawada, Teruo . E-mail: fat@kais.kyoto-u.ac.jp

    2005-11-18

    The peroxisome proliferator-activated receptor (PPAR) is one of the indispensable transcription factors for regulating lipid metabolism in various tissues. In our screening for natural compounds that activate PPAR using luciferase assays, a branched-carbon-chain alcohol (a component of chlorophylls), phytol, has been identified as a PPAR{alpha}-specific activator. Phytol induced the increase in PPAR{alpha}-dependent luciferase activity and the degree of in vitro binding of a coactivator, SRC-1, to GST-PPAR{alpha}. Moreover, the addition of phytol upregulated the expression of PPAR{alpha}-target genes at both mRNA and protein levels in PPAR{alpha}-expressing HepG2 hepatocytes. These findings indicate that phytol is functional as a PPAR{alpha} ligand and that it stimulates the expression of PPAR{alpha}-target genes in intact cells. Because PPAR{alpha} activation enhances circulating lipid clearance, phytol may be important in managing abnormalities in lipid metabolism.

  1. Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor γ Coactivator 1-α (PGC-1α) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver

    PubMed Central

    Buler, Marcin; Aatsinki, Sanna-Mari; Skoumal, Réka; Komka, Zsolt; Tóth, Miklós; Kerkelä, Risto; Georgiadi, Anastasia; Kersten, Sander; Hakkola, Jukka

    2012-01-01

    Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver. Microarray analysis revealed that PGC-1α up-regulated expression of several cytokines and cytokine receptors, including interleukin 15 receptor α (IL15Rα) and, even more importantly, anti-inflammatory interleukin 1 receptor antagonist (IL1Rn). Overexpression of PGC-1α and induction of PGC-1α by fasting, physical exercise, glucagon, or cAMP was associated with increased IL1Rn mRNA and protein expression in hepatocytes. Knockdown of PGC-1α by siRNA down-regulated cAMP-induced expression of IL1Rn in mouse hepatocytes. Furthermore, knockdown of peroxisome proliferator-activated receptor α (PPARα) attenuated IL1Rn induction by PGC-1α. Overexpression of PGC-1α, at least partially through IL1Rn, suppressed interleukin 1β-induced expression of acute phase proteins, C-reactive protein, and haptoglobin. Fasting and exercise also induced IL15Rα expression, whereas glucagon and cAMP resulted in reduction in IL15Rα mRNA levels. Finally, AMPK activator metformin and adenoviral overexpression of AMPK up-regulated IL1Rn and down-regulated IL15Rα in primary hepatocytes. We conclude that PGC-1α and AMPK alter inflammatory gene expression in liver and thus integrate energy homeostasis and inflammation. Induction of IL1Rn by PGC-1α and AMPK may be involved in the beneficial effects of exercise and caloric restriction and putative anti-inflammatory effects of metformin. PMID:22117073

  2. Energy-sensing factors coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase control expression of inflammatory mediators in liver: induction of interleukin 1 receptor antagonist.

    PubMed

    Buler, Marcin; Aatsinki, Sanna-Mari; Skoumal, Réka; Komka, Zsolt; Tóth, Miklós; Kerkelä, Risto; Georgiadi, Anastasia; Kersten, Sander; Hakkola, Jukka

    2012-01-13

    Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) and AMP-activated protein kinase (AMPK) may modulate inflammatory gene expression in liver. Microarray analysis revealed that PGC-1α up-regulated expression of several cytokines and cytokine receptors, including interleukin 15 receptor α (IL15Rα) and, even more importantly, anti-inflammatory interleukin 1 receptor antagonist (IL1Rn). Overexpression of PGC-1α and induction of PGC-1α by fasting, physical exercise, glucagon, or cAMP was associated with increased IL1Rn mRNA and protein expression in hepatocytes. Knockdown of PGC-1α by siRNA down-regulated cAMP-induced expression of IL1Rn in mouse hepatocytes. Furthermore, knockdown of peroxisome proliferator-activated receptor α (PPARα) attenuated IL1Rn induction by PGC-1α. Overexpression of PGC-1α, at least partially through IL1Rn, suppressed interleukin 1β-induced expression of acute phase proteins, C-reactive protein, and haptoglobin. Fasting and exercise also induced IL15Rα expression, whereas glucagon and cAMP resulted in reduction in IL15Rα mRNA levels. Finally, AMPK activator metformin and adenoviral overexpression of AMPK up-regulated IL1Rn and down-regulated IL15Rα in primary hepatocytes. We conclude that PGC-1α and AMPK alter inflammatory gene expression in liver and thus integrate energy homeostasis and inflammation. Induction of IL1Rn by PGC-1α and AMPK may be involved in the beneficial effects of exercise and caloric restriction and putative anti-inflammatory effects of metformin.

  3. ABCD2 Alters Peroxisome Proliferator-Activated Receptor α Signaling In Vitro, but Does Not Impair Responses to Fenofibrate Therapy in a Mouse Model of Diet-Induced Obesity

    PubMed Central

    Liu, Xiaoxi; Liu, Jingjing; Liang, Shuang; Schlüter, Agatha; Fourcade, Stephane; Aslibekyan, Stella; Pujol, Aurora

    2014-01-01

    Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) α ligand that has been widely used as a lipid-lowering agent in the treatment of hypertriglyceridemia. ABCD2 (D2) is a peroxisomal long-chain acyl-CoA transporter that is highly induced by fenofibrate in the livers of mice. To determine whether D2 is a modifier of fibrate responses, wild-type and D2-deficient mice were treated with fenofibrate for 14 days. The absence of D2 altered expression of gene clusters associated with lipid metabolism, including PPARα signaling. Using 3T3-L1 adipocytes, which express high levels of D2, we confirmed that knockdown of D2 modified genomic responses to fibrate treatment. We next evaluated the impact of D2 on effects of fibrates in a mouse model of diet-induced obesity. Fenofibrate treatment opposed the development of obesity, hypertriglyceridemia, and insulin resistance. However, these effects were unaffected by D2 genotype. We concluded that D2 can modulate genomic responses to fibrates, but that these effects are not sufficiently robust to alter the effects of fibrates on diet-induced obesity phenotypes. PMID:25123288

  4. Peroxisome Proliferator-Activated Receptor γ Deficiency in T Cells Accelerates Chronic Rejection by Influencing the Differentiation of CD4+ T Cells and Alternatively Activated Macrophages

    PubMed Central

    Ye, Ping; Cheng, Chao; Wu, Jie; Wang, Sihua; Sun, Yuan; Liu, Zheng; Xie, Aini; Xia, Jiahong

    2014-01-01

    Background In a previous study, activation of the peroxisome proliferator–activated receptor γ (PPARγ) inhibited chronic cardiac rejection. However, because of the complexity of chronic rejection and the fact that PPARγ is widely expressed in immune cells, the mechanism of the PPARγ - induced protective effect was unclear. Materials and Methods A chronic rejection model was established using B6.C-H-2bm12KhEg (H-2bm12) mice as donors, and MHC II-mismatched T-cell-specific PPARγ knockout mice or wild type (WT) littermates as recipients. The allograft lesion was assessed by histology and immunohistochemistry. T cells infiltrates in the allograft were isolated, and cytokines and subpopulations were detected using cytokine arrays and flow cytometry. Transcription levels in the allograft were measured by RT-PCR. In vitro, the T cell subset differentiation was investigated after culture in various polarizing conditions. PPARγ-deficient regularory T cells (Treg) were cocultured with monocytes to test their ability to induce alternatively activated macrophages (AAM). Results T cell-specific PPARγ knockout recipients displayed reduced cardiac allograft survival and an increased degree of pathology compared with WT littermates. T cell-specific PPARγ knockout resulted in more CD4+ T cells infiltrating into the allograft and altered the Th1/Th2 and Th17/Treg ratios. The polarization of AAM was also reduced by PPARγ deficiency in T cells through the action of Th2 and Treg. PPARγ-deficient T cells eliminated the pioglitazone-induced polarization of AAM and reduced allograft survival. Conclusions PPARγ-deficient T cells influenced the T cell subset and AAM polarization in chronic allograft rejection. The mechanism of PPARγ activation in transplantation tolerance could yield a novel treatment without side effects. PMID:25383620

  5. Transcription coactivator PRIP, the peroxisome proliferator-activated receptor (PPAR)-interacting protein, is redundant for the function of nuclear receptors PParalpha and CAR, the constitutive androstane receptor, in mouse liver.

    PubMed

    Sarkar, Joy; Qi, Chao; Guo, Dongsheng; Ahmed, Mohamed R; Jia, Yuzhi; Usuda, Nobuteru; Viswakarma, Navin; Rao, M Sambasiva; Reddy, Janardan K

    2007-01-01

    Disruption of the genes encoding for the transcription coactivators, peroxisome proliferator-activated receptor (PPAR)-interacting protein (PRIP/ASC-2/RAP250/TRBP/NRC) and PPAR-binding protein (PBP/TRAP220/DRIP205/MED1), results in embryonic lethality by affecting placental and multiorgan development. Targeted deletion of coactivator PBP gene in liver parenchymal cells (PBP(LIV-/-)) results in the near abrogation of the induction of PPARalpha and CAR (constitutive androstane receptor)-regulated genes in liver. Here, we show that targeted deletion of coactivator PRIP gene in liver (PRIP(LIV-/-)) does not affect the induction of PPARalpha-regulated pleiotropic responses, including hepatomegaly, hepatic peroxisome proliferation, and induction of mRNAs of genes involved in fatty acid oxidation system, indicating that PRIP is not essential for PPARalpha-mediated transcriptional activity. We also provide additional data to show that liver-specific deletion of PRIP gene does not interfere with the induction of genes regulated by nuclear receptor CAR. Furthermore, disruption of PRIP gene in liver did not alter zoxazolamine-induced paralysis, and acetaminophen-induced hepatotoxicity. Studies with adenovirally driven EGFP-CAR expression in liver demonstrated that, unlike PBP, the absence of PRIP does not prevent phenobarbital-mediated nuclear translocation/retention of the receptor CAR in liver in vivo and cultured hepatocytes in vitro. These results show that PRIP deficiency in liver does not interfere with the function of nuclear receptors PPARalpha and CAR. The dependence of PPARalpha- and CAR-regulated gene transcription on coactivator PBP but not on PRIP attests to the existence of coactivator selectivity in nuclear receptor function.

  6. MicroRNA-130b promotes cell proliferation and invasion by inhibiting peroxisome proliferator-activated receptor-γ in human glioma cells.

    PubMed

    Gu, Jian-Jun; Zhang, Jian-He; Chen, Hong-Jie; Wang, Shou-Sen

    2016-06-01

    MicroRNA-130b (miR-130b) is a novel tumor-related miRNA that has been found to be involved in several biological processes. However, there is limited evidence regarding the role of miR-130b in the tumorigenesis of human gliomas. In the present study, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays were used to quantify miR-130b expression levels in human glioma tissues and glioma cell lines (U251, U87, SNB19 and LN229). The expression level of miR-130b was found to be markedly higher in human glioma tissues than in non‑neoplastic brain specimens. Specifically, higher expression levels of miR‑130b were observed in the glioma cell lines, compared with those in normal human astrocytes (NHA). We also confirmed that miR‑130b interacted with the 3'-untranslated region of peroxisome proliferator‑activated receptor-γ (PPAR‑γ), which negatively affected the protein levels of E-cadherin. Furthermore, its effects on cell proliferation and invasion were examined using CCK8, colony formation, cell cycle and Transwell assays. We found that the upregulation of miR-130b induced cell proliferation, decreased the percentage of cells in the G0/G1 phase and enhanced the invasiveness of U251 glioma cells whereas the downregulation of miR-130b exerted opposing effects. Moreover, it was demonstrated that the downregulation of miR‑130b in U251 glioma cells restored the expression of PPAR-γ and E-cadherin, and inhibited the expression of β-catenin. Notably, PPAR-γ knockdown abolished the inhibitory effect of miR-130b inhibitor on the proliferation and invasivness of U251 cells. Taken together, these findings suggest that miR‑130b promotes the proliferation and invasion of U251 glioma cells by inhibiting PPAR-γ.

  7. Modeling Nonalcoholic Fatty Liver Disease with Human Pluripotent Stem Cell-Derived Immature Hepatocyte-Like Cells Reveals Activation of PLIN2 and Confirms Regulatory Functions of Peroxisome Proliferator-Activated Receptor Alpha

    PubMed Central

    Graffmann, Nina; Ring, Sarah; Kawala, Marie-Ann; Wruck, Wasco; Ncube, Audrey; Trompeter, Hans-Ingo

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD/steatosis) is a metabolic disease characterized by the incorporation of fat into hepatocytes. In this study, we developed an in vitro model for NAFLD based on hepatocyte-like cells (HLCs) differentiated from human pluripotent stem cells. We induced fat storage in these HLCs and detected major expression changes of metabolism-associated genes, as well as an overall reduction of liver-related microRNAs. We observed an upregulation of the lipid droplet coating protein Perilipin 2 (PLIN2), as well as of numerous genes of the peroxisome proliferator-activated receptor (PPAR) pathway, which constitutes a regulatory hub for metabolic processes. Interference with PLIN2 and PPARα resulted in major alterations in gene expression, especially affecting lipid, glucose, and purine metabolism. Our model recapitulates many metabolic changes that are characteristic for NAFLD. It permits the dissection of disease-promoting molecular pathways and allows us to investigate the influences of distinct genetic backgrounds on disease progression. PMID:27308945

  8. Transcriptome analyses demonstrate that Peroxisome Proliferator-Activated Receptor α (PPARα) activity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole, as possible mechanism of their toxicity and the gender differences.

    PubMed

    Hirata-Koizumi, Mutsuko; Ise, Ryota; Kato, Hirohito; Matsuyama, Takashi; Nishimaki-Mogami, Tomoko; Takahashi, Mika; Ono, Atsushi; Ema, Makoto; Hirose, Akihiko

    2016-01-01

    2-(2'-Hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), the Benzotriazole UV-stabilizer (BUVSs) known as UV-320, is widely used in plastic materials for protection against UV-irradiation. Previously, we reported that oral ingestion of HDBB induce hepatotoxicity including hepatocyte hypertrophy and necrosis in rats and, males was more susceptible compared with females in young rats while no sex-related difference was observed in preweaning rats. Phenotypes observed in our previous study imply involvement of peroxisome proliferator-activated receptor (PPAR) α in HDBB hepatotoxicity, however, direct evidence that HDBB can activate PPARα has not been provided and the mechanism which underlying the gender difference of HDBB hepatotoxicity was not clearly elucidated. Here, we conduct transcriptome analysis using microarray expression profiles in the livers of rats administered HDBB. PPARα agonist activity of HDBB was elucidated by comparison with gene expression data of typical PPARα agonist, i.e. clofibrate, WY-14643, gemfibrozil, and fenofibrate, from TG GATEs database. Moreover, we analyzed for PPARα mRNA expression in the liver of developing male and female rats. PPARα mRNA expression level was higher in males than in females on postnatal days (PNDs) 28 and 35, whereas no sex-related difference was found on PNDs 7 and 22. These results suggest that HDBB exerts its hepatotoxicity through the PPARα signal pathway and the sex-related difference in PPARα expression may contribute to the sex-related difference in susceptibility to hepatotoxicity. PMID:27665778

  9. An aqueous extract of Salacia oblonga root, a herb-derived peroxisome proliferator-activated receptor-alpha activator, by oral gavage over 28 days induces gender-dependent hepatic hypertrophy in rats.

    PubMed

    Rong, Xianglu; Kim, Moon Sun; Su, Ning; Wen, Suping; Matsuo, Yukimi; Yamahara, Johji; Murray, Michael; Li, Yuhao

    2008-06-01

    Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by natural and synthetic chemicals induces hepatic hypertrophy. An aqueous extract of Salacia oblonga root (SOW) is an Ayurvedic medicine with anti-diabetic and anti-obesity properties. In the present study, it was found that SOW (100, 300 and 900mg/kg, once daily by oral gavage over a 28 day period) elicited dose-related increases in liver weight (LW) by 1.6%, 13.4% and 42.5%, respectively, and in the ratio of LW to body weight by 8.8%, 16.7% and 40.2%, respectively, in male rats. These effects were less pronounced in females. SOW selectively increased liver mass in male rats but Sudan red staining was not different, which indicates that hepatic lipid accumulation was similar in both genders. However, SOW even at the highest dosage did not influence serum ALT and AST activities in male or female rats. Moreover, SOW was found to activate PPAR-alpha in human hepatoma-derived HepG2 cells, as evidenced by the upregulation of PPAR-alpha and acyl-CoA oxidase mRNA expression. Thus, SOW-dependent PPAR-alpha activation may precede the development of the gender difference in hepatic hypertrophy; this process may be influenced by sex hormone status. PMID:18397819

  10. Monascin attenuates oxidative stress-mediated lung inflammation via peroxisome proliferator-activated receptor-gamma (PPAR-γ) and nuclear factor-erythroid 2 related factor 2 (Nrf-2) modulation.

    PubMed

    Hsu, Wei-Hsuan; Lee, Bao-Hong; Pan, Tzu-Ming

    2014-06-11

    We speculated that peroxisome proliferator-activated receptor (PPAR)-γ agonists may modulate the oxidative stress pathway to ameliorate the development of airway inflammation. The effect of Monascus-fermented metabolite monascin (MS) and rosiglitazone (Rosi) on oxidative stress-induced lung inflammation was evaluated. Luciferase assay and DNA binding activity assay were used to point out that MS may be a novel PPAR-γ agonist and nuclear factor-erythroid 2 related factor 2 (Nrf-2) activator. We used hydrogen peroxide (H2O2) to induce inflammation in lung epithelial cells. MS and Rosi prevented H2O2-induced ROS generation in A549 epithelial cells through PPAR-γ translocation, avoiding inflammatory mediator expression via inhibiting nuclear factor (NF)-κB translocation. The regulatory ability of MS was abolished by siRNA against PPAR-γ. MS also elevated antioxidant enzyme expression via Nrf-2 activation. Both PPAR-γ and Nrf-2 might have benefits against lung inflammation. MS regulated PPAR-γ and Nrf-2 to improve lung oxidative inflammation. PMID:24865672

  11. Hypoxia-inducible factor 1 mediates hypoxia-induced cardiomyocyte lipid accumulation by reducing the DNA binding activity of peroxisome proliferator-activated receptor {alpha}/retinoid X receptor

    SciTech Connect

    Belanger, Adam J.; Luo Zhengyu; Vincent, Karen A.; Akita, Geoffrey Y.; Cheng, Seng H.; Gregory, Richard J.; Jiang Canwen

    2007-12-21

    In response to cellular hypoxia, cardiomyocytes adapt to consume less oxygen by shifting ATP production from mitochondrial fatty acid {beta}-oxidation to glycolysis. The transcriptional activation of glucose transporters and glycolytic enzymes by hypoxia is mediated by hypoxia-inducible factor 1 (HIF-1). In this study, we examined whether HIF-1 was involved in the suppression of mitochondrial fatty acid {beta}-oxidation in hypoxic cardiomyocytes. We showed that either hypoxia or adenovirus-mediated expression of a constitutively stable hybrid form (HIF-1{alpha}/VP16) suppressed mitochondrial fatty acid metabolism, as indicated by an accumulation of intracellular neutral lipid. Both treatments also reduced the mRNA levels of muscle carnitine palmitoyltransferase I which catalyzes the rate-limiting step in the mitochondrial import of fatty acids for {beta}-oxidation. Furthermore, adenovirus-mediated expression of HIF-1{alpha}/VP16 in cardiomyocytes under normoxic conditions also mimicked the reduction in the DNA binding activity of peroxisome proliferator-activated receptor {alpha} (PPAR{alpha})/retinoid X receptor (RXR), in the presence or absence of a PPAR{alpha} ligand. These results suggest that HIF-1 may be involved in hypoxia-induced suppression of fatty acid metabolism in cardiomyocytes by reducing the DNA binding activity of PPAR{alpha}/RXR.

  12. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

    PubMed

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention. PMID:26292284

  13. Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

    SciTech Connect

    Li, Jun; Kennedy, Lawrence J.; Shi, Yan; Tao, Shiwei; Ye, Xiang-Yang; Chen, Stephanie Y.; Wang, Ying; Hernndez, Andrs S.; Wang, Wei; Devasthale, Pratik V.; Chen, Sean; Lai, Zhi; Zhang, Hao; Wu, Shung; Smirk, Rebecca A.; Bolton, Scott A.; Ryono, Denis E.; Zhang, Huiping; Lim, Ngiap-Kie; Chen, Bang-Chi; Locke, Kenneth T.; O’Malley, Kevin M.; Zhang, Litao; Srivastava, Rai Ajit; Miao, Bowman; Meyers, Daniel S.; Monshizadegan, Hossain; Search, Debra; Grimm, Denise; Zhang, Rongan; Harrity, Thomas; Kunselman, Lori K.; Cap, Michael; Kadiyala, Pathanjali; Hosagrahara, Vinayak; Zhang, Lisa; Xu, Carrie; Li, Yi-Xin; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Krystek, Stanley R.; Blanar, Michael A.; Zahler, Robert; Mukherjee, Ranjan; Cheng, Peter T.W.; Tino, Joseph A.

    2010-04-12

    An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

  14. Boehmeria nivea Stimulates Glucose Uptake by Activating Peroxisome Proliferator-Activated Receptor Gamma in C2C12 Cells and Improves Glucose Intolerance in Mice Fed a High-Fat Diet

    PubMed Central

    Kim, Sung Hee; Sung, Mi Jeong; Park, Jae Ho; Yang, Hye Jeong; Hwang, Jin-Taek

    2013-01-01

    We examined the antidiabetic property of Boehmeria nivea (L.) Gaud. Ethanolic extract of Boehmeria nivea (L.) Gaud. (EBN) increased the uptake of 2-[N-(nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxy-d-glucose in C2C12 myotubes. To examine the mechanisms underlying EBN-mediated increase in glucose uptake, we examined the transcriptional activity and expression of peroxisome proliferator-activated receptor gamma (PPAR-γ), a pivotal target for glucose metabolism in C2C12 myotubes. We found that the EBN increased both the transcriptional activity and mRNA expression levels of PPAR-γ. In addition, we measured phosphorylation and expression levels of other targets of glucose metabolism, such as AMP-activated protein kinase (AMPK) and protein kinase B (Akt/PKB). We found that EBN did not alter the phosphorylation or expression levels of these proteins in a time- or dose-dependent manner, which suggested that EBN stimulates glucose uptake through a PPAR-γ-dependent mechanism. Further, we investigated the antidiabetic property of EBN using mice fed a high-fat diet (HFD). Administration of 0.5% EBN reduced the HFD-induced increase in body weight, total cholesterol level, and fatty liver and improved the impaired fasting glucose level, blood insulin content, and glucose intolerance. These results suggest that EBN had an antidiabetic effect in cell culture and animal systems and may be useful for preventing diabetes. PMID:23690860

  15. Methanolic leaf extract of Gymnema sylvestre augments glucose uptake and ameliorates insulin resistance by upregulating glucose transporter-4, peroxisome proliferator-activated receptor-gamma, adiponectin, and leptin levels in vitro

    PubMed Central

    Kumar, Puttanarasaiah Mahesh; Venkataranganna, Marikunte V.; Manjunath, Kirangadur; Viswanatha, Gollapalle L.; Ashok, Godavarthi

    2016-01-01

    Aims: The present study was undertaken to evaluate the effect of methanolic leaf extract of Gymnema sylvestre (MLGS) on glucose transport (GLUT) and insulin resistance in vitro. Materials and Methods: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) and GLUT-4 expression were assessed in L6 myotubes for concluding the GLUT activity, and adiponectin and leptin expression was studied in 3T3 L1 murine adipocyte cell line to determine the effect of MLGS (250-750 μg/ml) on insulin resistance. Results: The findings of the experiments have demonstrated a significant and dose-dependent increase in glucose uptake in all the tested concentrations of MLGS, further the glucose uptake activity of MLGS (750 μg/ml) was at par with rosiglitazone (50 μg/ml). Concomitantly, MLGS has shown enhanced GLUT-4 and PPAR-γ gene expressions in L6 myotubes. Furthermore, cycloheximide (CHX) had completely abolished the glucose uptake activity of MLGS when co-incubated, which further confirmed that glucose uptake activity of MLGS was linked to enhanced expression of GLUT-4 and PPAR-γ. In addition, in another experimental set, MLGS showed enhanced expression of adiponectin and leptin, thus confirms the ameliorative effect of MLGS on insulin resistance. Conclusion: These findings suggest that MLGS has an enhanced glucose uptake activity in L6 myotubes, and ameliorate the insulin resistance in 3T3 L1 murine adipocyte cell line in vitro. PMID:27104035

  16. Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation.

    PubMed

    Kim, Ki Young; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2007-09-01

    Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPARgamma activation in human lung cancers by using a novel PPARgamma agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARgamma activation selectively inhibited cell viability of non-small-cell lung cancer with little effect on small-cell lung cancer and normal lung cells. The cell death induced by PPARgamma activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non-small-cell lung cancer cell line. Reactive oxygen species (ROS) production was accompanied by increased expression of proline oxidase (POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNA interference treatment blocked PPARgamma-induced ROS formation and cytotoxicity, suggesting that POX plays a functional role in apoptosis through ROS formation. The apoptotic effects by the agonists were antagonized by bisphenol A diglycidyl ether, a PPARgamma antagonist, and by knockdown of PPARgamma expression, indicating the involvement of PPARgamma in these actions. The results of the present study suggest that PPARgamma activation induces apoptotic cell death in non-small-cell lung carcinoma mainly through ROS formation via POX induction.

  17. Peroxisome proliferator-activated receptor-γ agonist inhibits collagen synthesis in human keloid fibroblasts by suppression of early growth response-1 expression through upregulation of miR-543 expression

    PubMed Central

    Zhu, Hua-Yu; Bai, Wen-Dong; Wang, Hong-Tao; Xie, Song-Tao; Tao, Ke; Su, Lin-Lin; Liu, Jia-Qi; Yang, Xue-Kang; Li, Jun; Wang, Yun-Chuan; He, Ting; Han, Jun-Tao; Hu, Da-Hai

    2016-01-01

    A keloid is a benign skin tumor formed by an overgrowth of granulation tissue in affected patients. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists were reported to be able to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanism of PPAR-γ agonist troglitazone treatment for fibroblasts obtained from keloid patients. The data revealed that troglitazone treatment of keloid fibroblasts (KFs) downregulated the expression of early growth response-1 (Egr1) and collagen-1 (Col1). Level of Egr1 were closely associated with KF-induced fibrosis. The miRNA profiling data revealed that miR-543 was transcriptionally activated after troglitazone treatment. Bioinformatic analysis and experimental data showed that miR-543 was able to target Egr1. ELISA data confirmed that Col1 protein in the supernatant were modulated by the feedback regulatory axis of PPAR-γ agonist-induced miR-543 to inhibit Egr1 expression, whereas PPAR-γ antagonist treatment abolished such effect on Col1 suppression in KFs. This study demonstrated that the PPAR-γ agonist-mediated miR-543 and Egr1 signaling plays an important role in the suppression of collagen synthesis in KFs. Future in vivo studies are needed to confirm these in vitro data. PMID:27429849

  18. Peroxisome proliferator-activated receptor δ downregulates the expression of the receptor for advanced glycation end products and pro-inflammatory cytokines in the kidney of streptozotocin-induced diabetic mice.

    PubMed

    Liang, Yao-Jen; Chen, Siang-An; Jian, Jhih-Hao

    2011-05-18

    Activation of peroxisome proliferator-activated receptor δ (PPARδ) plays board beneficial effects in treating metabolic syndrome. The aim of this study is to examine whether PPARδ alters the expression of the receptor for advanced glycation end products (RAGE) and downstream pro-inflammatory cytokines in diabetic nephropathy. Streptozotocin-induced diabetic mice (STZ mice) were injected with a PPARδ agonist, L-165041 (5 μM/kg, intraperitoneal) once daily for 10 days and high glucose-treated cultured HEK cells were also used. After L-165041 treatment, serum TNFα, IL-6 and IL-1 levels were significantly decreased in STZ mice. RAGE mRNA and protein expression were both decreased by L-165041 in kidney tissues of STZ mice. The high glucose incubation increased NF-κB, RAGE and IL-6 expressions in HEK293 cells. These effects were inhibited by L-165041 and specific RAGE siRNA transfection. This study demonstrated that PPARδ may play a beneficial role in preventing diabetic nephropathy. Its downstream signaling may include RAGE and NF-κB pathway. Target on PPARδ will provide new meaningful therapies to patients with diabetic nephropathy.

  19. Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1

    PubMed Central

    den Besten, Gijs; Gerding, Albert; van Dijk, Theo H.; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K.; Reijngoud, Dirk-Jan; Bakker, Barbara M.

    2015-01-01

    The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention. PMID:26292284

  20. Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

    SciTech Connect

    Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

    2009-07-24

    The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}). Although nifedipine did not affect expression levels of PPAR-{gamma}, it increased the PPAR-{gamma} transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-{gamma} activation.

  1. Involvement of peroxisome proliferator-activated receptor β/δ (PPAR β/δ) in BDNF signaling during aging and in Alzheimer disease: possible role of 4-hydroxynonenal (4-HNE).

    PubMed

    Benedetti, Elisabetta; D'Angelo, Barbara; Cristiano, Loredana; Di Giacomo, Erica; Fanelli, Francesca; Moreno, Sandra; Cecconi, Francesco; Fidoamore, Alessia; Antonosante, Andrea; Falcone, Roberta; Ippoliti, Rodolfo; Giordano, Antonio; Cimini, Annamaria

    2014-01-01

    Aging and many neurological disorders, such as AD, are linked to oxidative stress, which is considered the common effector of the cascade of degenerative events. In this phenomenon, reactive oxygen species play a fundamental role in the oxidative decomposition of polyunsaturated fatty acids, resulting in the formation of a complex mixture of aldehydic end products, such as malondialdehyde, 4-hydroxynonenal, and other alkenals. Interestingly, 4-HNE has been indicated as an intracellular agonist of peroxisome proliferator-activated receptor β/δ. In this study, we examined, at early and advanced AD stages (3, 9, and 18 months), the pattern of 4-HNE and its catabolic enzyme glutathione S-transferase P1 in relation to the expression of PPARβ/δ, BDNF signaling, as mRNA and protein, as well as on their pathological forms (i.e., precursors or truncated forms). The data obtained indicate a novel detrimental age-dependent role of PPAR β/δ in AD by increasing pro-BDNF and decreasing BDNF/TrkB survival pathways, thus pointing toward the possibility that a specific PPARβ/δ antagonist may be used to counteract the disease progression. PMID:24621497

  2. Agonist-induced activation releases peroxisome proliferator-activated receptor beta/delta from its inhibition by palmitate-induced nuclear factor-kappaB in skeletal muscle cells.

    PubMed

    Jové, Mireia; Laguna, Juan C; Vázquez-Carrera, Manuel

    2005-05-01

    The mechanisms by which elevated levels of free fatty acids cause insulin resistance are not well understood, but there is a strong correlation between insulin resistance and intramyocellular lipid accumulation in skeletal muscle. In addition, accumulating evidence suggests a link between inflammation and type 2 diabetes. The aim of this work was to study whether the exposure of skeletal muscle cells to palmitate affected peroxisome proliferator-activated receptor (PPAR) beta/delta activity. Here, we report that exposure of C2C12 skeletal muscle cells to 0.75 mM palmitate reduced (74%, P<0.01) the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK-4), which is involved in fatty acid utilization. This reduction was not observed in the presence of the PPARbeta/delta agonist L-165041. This drug prevented palmitate-induced nuclear factor (NF)-kappaB activation. Increased NF-kappaB activity after palmitate exposure was associated with enhanced protein-protein interaction between PPARbeta/delta and p65. Interestingly, treatment with the PPARbeta/delta agonist L-165041 completely abolished this interaction. These results indicate that palmitate may reduce fatty acid utilization in skeletal muscle cells by reducing PPARbeta/delta signaling through increased NF-kappaB activity.

  3. Impaired coactivator activity of the Gly{sub 482} variant of peroxisome proliferator-activated receptor {gamma} coactivator-1{alpha} (PGC-1{alpha}) on mitochondrial transcription factor A (Tfam) promoter

    SciTech Connect

    Choi, Yon-Sik; Hong, Jung-Man; Lim, Sunny; Ko, Kyung Soo; Pak, Youngmi Kim . E-mail: ymkimpak@amc.seoul.kr

    2006-06-09

    Mitochondrial dysfunction may cause diabetes or insulin resistance. Peroxisome proliferation-activated receptor-{gamma} (PPAR-{gamma}) coactivator-1 {alpha} (PGC-1{alpha}) increases mitochondrial transcription factor A (Tfam) resulting in mitochondrial DNA content increase. An association between a single nucleotide polymorphism (SNP), G1444A(Gly482Ser), of PGC-1{alpha} coding region and insulin resistance has been reported in some ethnic groups. In this study, we investigated whether a change of glycine to serine at codon 482 of PGC-1{alpha} affected the Tfam promoter activity. The cDNA of PGC-1{alpha} variant bearing either glycine or serine at 482 codon was transfected into Chang human hepatocyte cells. The PGC-1{alpha} protein bearing glycine had impaired coactivator activity on Tfam promoter-mediated luciferase. We analyzed the PGC-1{alpha} genotype G1444A and mitochondrial DNA (mtDNA) copy number from 229 Korean leukocyte genomic DNAs. Subjects with Gly/Gly had a 20% lower amount of peripheral blood mtDNA than did subjects with Gly/Ser and Ser/Ser (p < 0.05). No correlation was observed between diabetic parameters and PGC-1{alpha} genotypes in Koreans. These results suggest that PGC-1{alpha} variants with Gly/Gly at 482nd amino acid may impair the Tfam transcription, a regulatory function of mitochondrial biogenesis, resulting in dysfunctional mtDNA replication.

  4. Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1)-deacetylase and peroxisome proliferator-activated receptors (PPARs).

    PubMed

    Jin, Taewon; Kim, Oh Yoen; Shin, Min-Jeong; Choi, Eun Young; Lee, Sung Sook; Han, Ye Sun; Chung, Ji Hyung

    2014-10-29

    Adiponectin, an adipokine, has been described as showing physiological benefits against obesity-related malfunctions and vascular dysfunction. Several natural compounds that promote the expression and secretion of adipokines in adipocytes could be useful for treating metabolic disorders. This study investigated the effect of fisetin, a dietary flavonoid, on the regulation of adiponectin in adipocytes using 3T3-L1 preadipocytes. The expression and secretion of adiponectin increased in 3T3-L1 cells upon treatment with fisetin in a dose-dependent manner. Fisetin-induced adiponectin secretion was inhibited by peroxisome proliferator-activated receptor (PPAR) antagonists. It was also revealed that fisetin increased the activities of PPARs and silent mating type information regulation 2 homologue 1 (SIRT1) in a dose-dependent manner. Furthermore, the up-regulation of adiponectin and the activation of PPARs induced by fisetin were prevented by a SIRT1 inhibitor. Fisetin also promoted deacetylation of PPAR γ coactivator 1 (PGC-1) and its interaction with PPARs. SIRT knockdown by siRNA significantly decreased both adiponectin production and PPARs-PGC-1 interaction. These results provide evidence that fisetin promotes the gene expression of adiponectin through the activation of SIRT1 and PPARs in adipocytes.

  5. Peroxisome proliferator-activated receptor-γ agonist inhibits collagen synthesis in human keloid fibroblasts by suppression of early growth response-1 expression through upregulation of miR-543 expression.

    PubMed

    Zhu, Hua-Yu; Bai, Wen-Dong; Wang, Hong-Tao; Xie, Song-Tao; Tao, Ke; Su, Lin-Lin; Liu, Jia-Qi; Yang, Xue-Kang; Li, Jun; Wang, Yun-Chuan; He, Ting; Han, Jun-Tao; Hu, Da-Hai

    2016-01-01

    A keloid is a benign skin tumor formed by an overgrowth of granulation tissue in affected patients. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists were reported to be able to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanism of PPAR-γ agonist troglitazone treatment for fibroblasts obtained from keloid patients. The data revealed that troglitazone treatment of keloid fibroblasts (KFs) downregulated the expression of early growth response-1 (Egr1) and collagen-1 (Col1). Level of Egr1 were closely associated with KF-induced fibrosis. The miRNA profiling data revealed that miR-543 was transcriptionally activated after troglitazone treatment. Bioinformatic analysis and experimental data showed that miR-543 was able to target Egr1. ELISA data confirmed that Col1 protein in the supernatant were modulated by the feedback regulatory axis of PPAR-γ agonist-induced miR-543 to inhibit Egr1 expression, whereas PPAR-γ antagonist treatment abolished such effect on Col1 suppression in KFs. This study demonstrated that the PPAR-γ agonist-mediated miR-543 and Egr1 signaling plays an important role in the suppression of collagen synthesis in KFs. Future in vivo studies are needed to confirm these in vitro data. PMID:27429849

  6. Short communication: the pharmacological peroxisome proliferator-activated receptor α agonist WY-14,643 increases expression of novel organic cation transporter 2 and carnitine uptake in bovine kidney cells.

    PubMed

    Zhou, X; Wen, G; Ringseis, R; Eder, K

    2014-01-01

    Recent studies in rodents demonstrated that peroxisome proliferator-activated receptor α (PPARα), a central regulator of energy homeostasis, is an important transcriptional regulator of the gene encoding the carnitine transporter novel organic cation transporter 2 (OCTN2). Less is known with regard to the regulation of OCTN2 by PPARα and its role for carnitine transport in cattle, even though PPARα activation physiologically occurs in the liver of high-producing cows during early lactation. To explore the role of PPARα for OCTN2 expression and carnitine transport in cattle, we studied the effect of the PPARα activator WY-14,643 on the expression of OCTN2 in the presence and absence of PPARα antagonists and on OCTN2-mediated carnitine transport in the Madin-Darby bovine kidney (MDBK) cell line. The results show that WY-14,643 increases mRNA and protein levels of OCTN2, whereas co-treatment of MDBK cells with WY-14,643 and the PPARα antagonist GW6471 blocks the WY-14,643-induced increase in mRNA and protein levels of OCTN2 in bovine cells. In addition, treatment of MDBK cells with WY-14,643 stimulates specifically Na(+)-dependent carnitine uptake in MDBK cells, which is likely the consequence of the increased carnitine transport capacity of cells due to the elevated expression of OCTN2. In conclusion, our results indicate that OCTN2 expression and carnitine transport in cattle, as in rodents, are regulated by PPARα.

  7. A peroxisome proliferator-activated receptor ligand MCC-555 imparts anti-proliferative response in pancreatic cancer cells by PPARgamma-independent up-regulation of KLF4

    SciTech Connect

    Min, Kyung-Won; Zhang, Xiaobo; Imchen, Temjenmongla; Baek, Seung Joon

    2012-09-01

    MCC-555 is a novel PPARα/γ dual ligand of the thiazolidinedione class and was recently developed as an anti-diabetic drug with unique properties. MCC-555 also has anti-proliferative activity through growth inhibition and apoptosis induction in several cancer cell types. Our group has shown that MCC-555 targets several proteins in colorectal tumorigenesis including nonsteroidal anti-inflammatory drug (NSAID)-activated gene (NAG-1) which plays an important role in chemoprevention responsible for chemopreventive compounds. NAG-1 is a member of the TGF-β superfamily and is involved in tumor progression and development; however, NAG-1's roles in pancreatic cancer have not been studied. In this report, we found that MCC-555 alters not only NAG-1 expression, but also p21 and cyclin D1 expression. NAG-1 and p21 expression was not blocked by PPARγ-specific antagonist GW9662, suggesting that MCC-555-induced NAG-1 and p21 expression is independent of PPARγ activation. However, decreasing cyclin D1 by MCC-555 seems to be affected by PPARγ activation. Further, we found that the GC box located in the NAG-1 promoter play an important role in NAG-1 transactivation by MCC-555. Subsequently, we screened several transcription factors that may bind to the GC box region in the NAG-1 promoter and found that KLF4 potentially binds to this region. Expression of KLF4 precedes NAG-1 and p21 expression in the presence of MCC-555, whereas blocking KLF4 expression using specific KLF4 siRNA showed that both NAG-1 and p21 expression by MCC-555 was blocked. In conclusion, MCC-555's actions on anti-proliferation involve both PPARγ-dependent and -independent pathways, thereby enhancing anti-tumorigenesis in pancreatic cancer cells. -- Highlights: ► PPARα/γ ligand MCC-555 exhibits anti-proliferative activity in pancreatic cancer cells. ► MCC-555 affects KLF4 expression following by NAG-1 and p21 expression in a PPARγ independent manner. ► MCC-555 also affects cyclin D1 down

  8. Peroxisome proliferator-activated receptor-γ agonist troglitazone suppresses transforming growth factor-β1 signalling through miR-92b upregulation-inhibited Axl expression in human keloid fibroblasts in vitro

    PubMed Central

    Zhu, Hua-Yu; Bai, Wen-Dong; Li, Jun; Tao, Ke; Wang, Hong-Tao; Yang, Xue-Kang; Liu, Jia-Qi; Wang, Yun-Chuan; He, Ting; Xie, Song-Tao; Hu, Da-Hai

    2016-01-01

    Keloid, a skin benign tumor, is characterized by overgrowth of fibroblasts and the excessive deposition of extracellular matrix in wounded skin. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist was recently evaluated to inhibit fibrosis. This study explored the underlying mechanisms. Fibroblasts isolated from 25 keloid patients (KFs) and fibroblasts isolated from healthy controls (NSFBs) were also subjected to treatment with PPAR-γ agonist troglitazone and antagonist GW9662 or for transfection with miR-92 mimics or inhibitor, Axl siRNA, and miR-92b or Axl promoter constructs, as well as being subjected to qRT-PCR, ELISA, Western blot, protein array, luciferase, and ChIP assays. The data demonstrated that TGF-β1 and Axl proteins were significantly elevated in samples from keloid patients, while troglitazone treatment significantly reduced levels of TGF-β1 and Axl mRNA and proteins in KFs. Moreover, knockdown of Axl expression reduced expression of TGF-β1 and its pathway genes (such as α-SMA and Snail). PPAR-γ regulation of Axl expression was through transcriptional activation of miR-92b. miR-92b expression downregulated Axl expression at both mRNA and protein levels, whereas GW9662 completely reversed the inhibitory effects of miR-92b mimics on Axl expression. Gene ontology analysis of miR-92b targeting genes showed that TGF-β and Axl were both potential targets of miR-92b, as confirmed by luciferase assay. These findings demonstrated that PPAR-γ-induced miR-92b expression inhibited Axl expression and in turn reduced expression of TGF-β1 and the downstream genes in KFs, suggesting that targeting of this novel gene pathway may be useful for therapeutic control of fibrosis or keloid.

  9. Aldo-keto reductase 1B10 promotes development of cisplatin resistance in gastrointestinal cancer cells through down-regulating peroxisome proliferator-activated receptor-γ-dependent mechanism.

    PubMed

    Matsunaga, Toshiyuki; Suzuki, Ayaka; Kezuka, Chihiro; Okumura, Naoko; Iguchi, Kazuhiro; Inoue, Ikuo; Soda, Midori; Endo, Satoshi; El-Kabbani, Ossama; Hara, Akira; Ikari, Akira

    2016-08-25

    Cisplatin (cis-diamminedichloroplatinum, CDDP) is one of the most effective chemotherapeutic drugs that are used for treatment of patients with gastrointestinal cancer cells, but its continuous administration often evokes the development of chemoresistance. In this study, we investigated alterations in antioxidant molecules and functions using a newly established CDDP-resistant variant of gastric cancer MKN45 cells, and found that aldo-keto reductase 1B10 (AKR1B10) is significantly up-regulated with acquisition of the CDDP resistance. In the nonresistant MKN45 cells, the sensitivity to cytotoxic effect of CDDP was decreased and increased by overexpression and silencing of AKR1B10, respectively. In addition, the AKR1B10 overexpression markedly suppressed accumulation and cytotoxicity of 4-hydroxy-2-nonenal that is produced during lipid peroxidation by CDDP treatment, suggesting that the enzyme acts as a crucial factor for facilitation of the CDDP resistance through inhibiting induction of oxidative stress by the drug. Transient exposure to CDDP and induction of the CDDP resistance decreased expression of peroxisome proliferator-activated receptor-γ (PPARγ) in MKN45 and colon cancer LoVo cells. Additionally, overexpression of PPARγ in the cells elevated the sensitivity to the CDDP toxicity, which was further augmented by concomitant treatment with a PPARγ ligand rosiglitazone. Intriguingly, overexpression of AKR1B10 in the cells resulted in a decrease in PPARγ expression, which was recovered by addition of an AKR1B10 inhibitor oleanolic acid, inferring that PPARγ is a downstream target of AKR1B10-dependent mechanism underlying the CDDP resistance. Combined treatment with the AKR1B10 inhibitor and PPARγ ligand elevated the CDDP sensitivity, which was almost the same level as that in the parental cells. These results suggest that combined treatment with the AKR1B10 inhibitor and PPARγ ligand is an effective adjuvant therapy for overcoming CDDP resistance of

  10. The peroxisome proliferator-activated receptor α agonist, AZD4619, induces alanine aminotransferase-1 gene and protein expression in human, but not in rat hepatocytes: Correlation with serum ALT levels.

    PubMed

    Thulin, Petra; Bamberg, Krister; Buler, Marcin; Dahl, Björn; Glinghammar, Björn

    2016-09-01

    Alanine aminotransferase (ALT) in serum is the standard biomarker for liver injury. We have previously described a clinical trial with a novel selective peroxisome proliferator-activated receptor α (PPARα) agonist (AZD4619), which unexpectedly caused increased serum levels of ALT in treated individuals without any other evidence of liver injury. We pinpointed a plausible mechanism through which AZD4619 could increase serum ALT levels; namely through the PPARα-specific activation of the human ALT1 gene at the transcriptional level. In the present study, we present data from the preceding rat toxicity study, demonstrating that AZD4619 had no effect on rat serum ALT activity levels, and further experiments were performed to elucidate the mechanisms responsible for this species-related difference. Our results revealed that AZD4619 increased ALT1 protein expression in a dose-dependent manner in human, but not in rat primary hepatocytes. Cloning of the human and rat ALT1 promoters into luciferase vectors confirmed that AZD4619 induced only the human, but not the rat ALT1 gene promoter in a dose-dependent manner. In PPARα-GAL4 reporter gene assays, AZD4619 was >100-fold more potent on the human vs. rat PPARα levels, explaining the differences in induction of the ALT1 gene between the species at the concentration range tested. These data demonstrate the usefulness of the human and rat ALT1 reporter gene assays for testing future drug candidates at the preclinical stage. In drug discovery projects, these assays elucidate whether elevations in ALT levels observed in vivo or in the clinic are due to metabolic effects rather than a toxic event in the liver. PMID:27430334

  11. A polymorphic autoregulatory hormone response element in the human estrogen-related receptor alpha (ERRalpha) promoter dictates peroxisome proliferator-activated receptor gamma coactivator-1alpha control of ERRalpha expression.

    PubMed

    Laganière, Josée; Tremblay, Gilles B; Dufour, Catherine R; Giroux, Sylvie; Rousseau, François; Giguère, Vincent

    2004-04-30

    The orphan nuclear estrogen-related receptor alpha (ERRalpha) and transcriptional cofactor peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) are involved in the regulation of energy metabolism. Recently, extensive cross-talk between PGC-1alpha and ERRalpha has been demonstrated. The presence of PGC-1alpha is associated with an elevated expression of ERRalpha, and the two proteins can influence the transcriptional activities of one another. Using a candidate gene approach to detect regulatory variants within genes encoding nuclear receptors, we have identified a 23-bp sequence (ESRRA23) containing two nuclear receptor recognition half-site motifs that is present in 1-4 copies within the promoter of the human ESRRA gene encoding ERRalpha. The ESRRA23 sequence contains a functional ERR response element that is specifically bound by ERRalpha, and chromatin immunoprecipitation shows that endogenous ERRalpha occupies its own promoter in vivo. Strikingly, introduction of PGC-1alpha in HeLa cells by transient transfection induces the activity of the ESRRA promoter in a manner that is dependent on the presence of the ESRRA23 element and on its dosage. Coexpression of ERRalpha and PGC-1alpha results in a synergistic activation of the ESRRA promoter. In experiments using ERRalpha null fibroblasts, the ability of PGC-1alpha to stimulate the ESRRA promoter is considerably reduced but can be restored by addition of ERRalpha. Taken together, these results demonstrate that an interdependent ERRalpha/PGC-1alpha-based transcriptional pathway targets the ESRRA23 element to dictate the level of ERRalpha expression. This study further suggests that this regulatory polymorphism may provide differential responses to ERRalpha/PGC-1alpha-mediated metabolic cues in the human population.

  12. Wogonin prevents lipopolysaccharide-induced acute lung injury and inflammation in mice via peroxisome proliferator-activated receptor gamma-mediated attenuation of the nuclear factor-kappaB pathway.

    PubMed

    Yao, Jing; Pan, Di; Zhao, Yue; Zhao, Li; Sun, Jie; Wang, Yu; You, Qi-Dong; Xi, Tao; Guo, Qing-Long; Lu, Na

    2014-10-01

    Acute lung injury (ALI) from a variety of clinical disorders, characterized by diffuse inflammation, is a cause of acute respiratory failure that develops in patients of all ages. Previous studies reported that wogonin, a flavonoid-like chemical compound which was found in Scutellaria baicalensis, has anti-inflammatory effects in several inflammation models, but not in ALI. Here, the in vivo protective effect of wogonin in the amelioration of lipopolysaccharide (LPS) -induced lung injury and inflammation was assessed. In addition, the in vitro effects and mechanisms of wogonin were studied in the mouse macrophage cell lines Ana-1 and RAW264.7. In vivo results indicated that wogonin attenuated LPS-induced histological alterations. Peripheral blood leucocytes decreased in the LPS-induced group, which was ameliorated by wogonin. In addition, wogonin inhibited the production of several inflammatory cytokines, including tumour necrosis factor-α, interleukin-1β (IL-1β) and IL-6, in the bronchoalveolar lavage fluid and lung tissues after LPS challenge, while the peroxisome proliferator-activated receptor γ (PPARγ) inhibitor GW9662 reversed these effects. In vitro results indicated that wogonin significantly decreased the secretion of IL-6, IL-1β and tumour necrosis factor-α in Ana-1 and RAW264.7 cells, which was suppressed by transfection of PPARγ small interfering RNA and GW9662 treatment. Moreover, wogonin activated PPARγ, induced PPARγ-mediated attenuation of the nuclear translocation and the DNA-binding activity of nuclear factor-κB in vivo and in vitro. In conclusion, all of these results showed that wogonin may serve as a promising agent for the attenuation of ALI-associated inflammation and pathology by regulating the PPARγ-involved nuclear factor-κB pathway. PMID:24766487

  13. Peroxisome proliferator-activated receptor alpha1 in yellow catfish Pelteobagrus fulvidraco: molecular characterization, mRNA tissue expression and transcriptional regulation by insulin in vivo and in vitro.

    PubMed

    Zheng, Jia-Lang; Zhuo, Mei-Qin; Luo, Zhi; Song, Yu-Feng; Pan, Ya-Xiong; Huang, Chao; Hu, Wei; Chen, Qi-Liang

    2015-05-01

    Peroxisome proliferator-activated receptor alpha1 (PPARα1) cDNA was isolated from liver of yellow catfish Pelteobagrus fulvidraco by RT-PCR and RACE. Its molecular characterization, tissue expression and transcriptional regulation by insulin in vitro and in vivo were determined. PPARα1 mRNA covered 1879 bp, with an open reading frame (ORF) of 1410 bp encoding 469 amino acid residues, a 5'-untranslated region (UTR) of 49 bp, and a 3'-UTR of 421 bp. PPARα1 consisted of 4 domains, the A/B domain, DNA-binding domain (DBD), D domain, and ligand-binding domain (LBD). The predicted tertiary structure of yellow catfish PPARα1 showed an increased size of the main cavity that was made up of side chains from helices 3, 5, 10, 11, and 12. Changes of PPARα1 structure might affect binding of mammalian PPARα1-specific ligand and cofactor in yellow catfish and may endow yellow catfish PPARα1 with new ligand-independent or -dependent transactivation activity. PPARα1 was differentially expressed in various tissues during development. Furthermore, intraperitoneal injection in vivo and incubation in vitro of insulin reduced the mRNA expression of PPARα1 in the liver and hepatocytes of yellow catfish. Based on the observation above, the present study provides evidence that PPARα1 is differentially expressed within and among tissues during three developmental stages and also regulated by insulin both in vivo and in vitro, which warrants further investigation of PPARα1 physiological function in fish. PMID:25645400

  14. Ligand-independent activation of peroxisome proliferator-activated receptor-gamma by insulin and C-peptide in kidney proximal tubular cells: dependent on phosphatidylinositol 3-kinase activity.

    PubMed

    Al-Rasheed, Nawal M; Chana, Ravinder S; Baines, Richard J; Willars, Gary B; Brunskill, Nigel J

    2004-11-26

    Peroxisome proliferator-activated receptor gamma (PPARgamma) has key roles in the regulation of adipogenesis, inflammation, and lipid and glucose metabolism. C-peptide is believed to be inert and without appreciable biological functions. Recent studies suggest that C-peptide possesses multiple functions. The present study investigated the effects of insulin and C-peptide on PPARgamma transcriptional activity in opossum kidney proximal tubular cells. Both insulin and C-peptide induced a concentration-dependent stimulation of PPARgamma transcriptional activity. Both agents substantially augmented thiazolidinedione-stimulated PPARgamma transcriptional activity. Neither insulin nor C-peptide had any effect on the expression levels of PPARgamma. GW9662, a PPARgamma antagonist, blocked PPARgamma activation by thiazolidinediones but had no effect on either insulin- or C-peptide-stimulated PPARgamma transcriptional activity. Co-transfection of opossum kidney cells with dominant negative mitogen-activated protein kinase kinase significantly depressed basal PPARgamma transcriptional activity but had no effect on that induced by either insulin or C-peptide. Both insulin- and C-peptide-stimulated PPARgamma transcriptional activity were attenuated by wortmannin and by expression of a dominant negative phosphatidylinositol (PI) 3-kinase p85 regulatory subunit. In addition PI 3-kinase-dependent phosphorylation of PPARgamma was observed after stimulation by C-peptide or insulin. C-peptide effects but not insulin on PPARgamma transcriptional activity were abolished by pertussis toxin pretreatment. Finally both C-peptide and insulin positively control the expression of the PPARgamma-regulated CD36 scavenger receptor in human THP-1 monocytes. We concluded that insulin and C-peptide can stimulate PPARgamma activity in a ligand-independent fashion and that this effect is mediated by PI 3-kinase. These results support a new and potentially important physiological role for C-peptide in

  15. Coordinate Functional Regulation between Microsomal Prostaglandin E Synthase-1 (mPGES-1) and Peroxisome Proliferator-activated Receptor γ (PPARγ) in the Conversion of White-to-brown Adipocytes*

    PubMed Central

    García-Alonso, Verónica; López-Vicario, Cristina; Titos, Esther; Morán-Salvador, Eva; González-Périz, Ana; Rius, Bibiana; Párrizas, Marcelina; Werz, Oliver; Arroyo, Vicente; Clària, Joan

    2013-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated nuclear receptor and a master regulator of adipogenesis. Microsomal prostaglandin E (PGE) synthase-1 (mPGES-1) is an inducible enzyme that couples with cyclooxygenase-2 for the biosynthesis of PGE2. In this study we demonstrate the existence of a coordinate functional interaction between PPARγ and mPGES-1 in controlling the process of pre-adipocyte differentiation in white adipose tissue (WAT). Adipocyte-specific PPARγ knock-out mice carrying an aP2 promoter-driven Cre recombinase transgene showed a blunted response to the adipogenic effects of a high fat diet. Pre-adipocytes from these knock-out mice showed loss of PPARγ and were resistant to rosiglitazone-induced WAT differentiation. In parallel, WAT from these mice showed increased expression of uncoupling protein 1, a mitochondrial enzyme that dissipates chemical energy as heat. Adipose tissue from mice lacking PPARγ also showed mPGES-1 up-regulation and increased PGE2 levels. In turn, PGE2 suppressed PPARγ expression and blocked rosiglitazone-induced pre-adipocyte differentiation toward white adipocytes while directly elevating uncoupling protein 1 expression and pre-adipocyte differentiation into mature beige/brite adipocytes. Consistently, pharmacological mPGES-1 inhibition directed pre-adipocyte differentiation toward white adipocytes while suppressing differentiation into beige/brite adipocytes. This browning effect was reproduced in knockdown experiments using a siRNA directed against mPGES-1. The effects of PGE2 on pre-adipocyte differentiation were not seen in mice lacking PPARγ in adipose tissue and were not mirrored by other eicosanoids (i.e. leukotriene B4). Taken together, these findings identify PGE2 as a key regulator of white-to-brown adipogenesis and suggest the existence of a coordinate regulation of adipogenesis between PPARγ and mPGES-1. PMID:23943621

  16. MicroRNA-27b plays a role in pulmonary arterial hypertension by modulating peroxisome proliferator-activated receptor γ dependent Hsp90-eNOS signaling and nitric oxide production

    SciTech Connect

    Bi, Rui; Bao, Chunrong; Jiang, Lianyong; Liu, Hao; Yang, Yang; Mei, Ju; Ding, Fangbao

    2015-05-01

    Pulmonary artery endothelial dysfunction is associated with pulmonary arterial hypertension (PAH). Based on recent studies showing that microRNA (miR)-27b is aberrantly expressed in PAH, we hypothesized that miR-27b may contribute to pulmonary endothelial dysfunction and vascular remodeling in PAH. The effect of miR-27b on pulmonary endothelial dysfunction and the underlying mechanism were investigated in human pulmonary artery endothelial cells (HPAECs) in vitro and in a monocrotaline (MCT)-induced model of PAH in vivo. miR-27b expression was upregulated in MCT-induced PAH and inversely correlated with the levels of peroxisome proliferator-activated receptor (PPAR)-γ, and miR-27b inhibition attenuated MCT-induced endothelial dysfunction and remodeling and prevented PAH associated right ventricular hypertrophy and systolic pressure in rats. PPARγ was confirmed as a direct target of miR-27b in HPAECs and shown to mediate the effect of miR-27b on the disruption of endothelial nitric oxide synthase (eNOS) coupling to Hsp90 and the suppression of NO production associated with the PAH phenotype. We showed that miR-27b plays a role endothelial function and NO release and elucidated a potential mechanism by which miR-27b regulates Hsp90-eNOS and NO signaling by modulating PPARγ expression, providing potential therapeutic targets for the treatment of PAH. - Highlights: • miR-27b plays a role in endothelial function and NO release. • miR-27b inhibition ameliorates MCT-induced endothelial dysfunction and PAH. • miR-27b targets PPARγ in HPAECs. • miR-27b regulates PPARγ dependent Hsp90-eNOS and NO signaling.

  17. Berberine-improved visceral white adipose tissue insulin resistance associated with altered sterol regulatory element-binding proteins, liver x receptors, and peroxisome proliferator-activated receptors transcriptional programs in diabetic hamsters.

    PubMed

    Li, Guo-Sheng; Liu, Xu-Han; Zhu, Hua; Huang, Lan; Liu, Ya-Li; Ma, Chun-Mei; Qin, Chuan

    2011-01-01

    The diabetic "lipotoxicity" hypothesis presents that fat-induced visceral white adipose tissue insulin resistance plays a central role in the pathogenesis of type 2 diabetes. Berberine, a hypolipidemic agent, has been reported to have antidiabetic activities. The molecular mechanisms for this property are, however, not well clarified. Therefore in this study type 2 diabetic hamsters were induced by high-fat diet with low-dose streptozotocin. Then, we investigated the gene expression alterations and explored the molecular mechanisms underlying the therapeutic effect of berberine on fat-induced visceral white adipose tissue insulin resistance in diabetic hamsters by microarray analysis followed by real-time reverse transcription-polymerase chain reaction (RT-PCR) confirmation. Type 2 diabetic hamsters exhibited hyperglycemia and relative hyperinsulinemia, glucose intolerance, insulin resistance, intra-adipocyte lipid accumulation, significant increase in body weight and visceral white adipose tissue weight, abnormal serum adipokines levels, and deleterious dyslipidemia. Furthermore, they had increased sterol regulatory element-binding proteins (SREBPs) expression and decreased liver X receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression in visceral white adipose tissue. After 9-week berberine treatment, fat-induced insulin resistance and diabetic phenotype in type 2 diabetic hamsters were significantly improved. Compared with diabetic hamsters, expression of LXRs and PPARs significantly increased and SREBPs significantly decreased in visceral white adipose tissue from berberine-treated diabetic hamsters. These results suggest that altered visceral white adipose tissue LXRs, PPARs, and SREBPs transcriptional programs are involved in the therapeutic mechanisms of berberine on fat-induced visceral white adipose tissue insulin resistance in type 2 diabetic hamsters.

  18. Nymphaea nouchali Burm. f. hydroalcoholic seed extract increases glucose consumption in 3T3-L1 adipocytes through activation of peroxisome proliferator-activated receptor gamma and insulin sensitization.

    PubMed

    Parimala, Mabel; Debjani, M; Vasanthi, Hannah Rachel; Shoba, Francis Gricilda

    2015-01-01

    Nymphaea nouchali Burm. f. (Family - Nymphaeaceae) is a well-known medicinal plant used in the Indian ayurvedic system of medicine for treating diabetes. The seeds especially have been prescribed for diabetes. The hydroalcoholic extract of N. nouchali seeds has been demonstrated to possess anti-hyperglycemic effects in diabetic rats, but the functional mechanism remains unknown. The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ) is noted to play an important role in glucose and lipid homeostasis. This study was hence focused in evaluating the effect of the extract on PPARγ activation, adipocyte differentiation, and glucose consumption in 3T3-L1 cells. Cell viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), followed by adipogenesis assay using Oil Red O technique. Glucose consumption of preadipocytes and adipocytes in the presence of the extract was also determined. Real-time polymerase chain reaction was performed to identify the expression of genes involved in glucose consumption in the adipocytes. MTT assay confirmed the extract to be nontoxic, and Oil Red O staining confirmed enhanced adipocyte differentiation of 3T3-L1 cells in a dose-dependent manner. The extract also increased the expression of PPARγ target gene, which in turn enhanced the expression of GLUT-4. The data, therefore, suggests that N. nouchali seed extract promotes adipocyte differentiation and glucose consumption by inducing PPARγ activation, which in turn increases mRNA GLUT-4 expression and subsequently enhances insulin-responsiveness in insulin target tissues.

  19. Nymphaea nou