PPAR Research http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2014 , Hindawi Publishing Corporation . All rights reserved. TRPV1 Activation Attenuates High-Salt Diet-Induced Cardiac Hypertrophy and Fibrosis through PPAR-δ Upregulation Thu, 24 Jul 2014 10:10:11 +0000 http://www.hindawi.com/journals/ppar/2014/491963/ High-salt diet-induced cardiac hypertrophy and fibrosis are associated with increased reactive oxygen species production. Transient receptor potential vanilloid type 1 (TRPV1), a specific receptor for capsaicin, exerts a protective role in cardiac remodeling that resulted from myocardial infarction, and peroxisome proliferation-activated receptors δ (PPAR-δ) play an important role in metabolic myocardium remodeling. However, it remains unknown whether activation of TRPV1 could alleviate cardiac hypertrophy and fibrosis and the effect of cross-talk between TRPV1 and PPAR-δ on suppressing high-salt diet-generated oxidative stress. In this study, high-salt diet-induced cardiac hypertrophy and fibrosis are characterized by significant enhancement of HW/BW%, LVEDD, and LVESD, decreased FS and EF, and increased collagen deposition. These alterations were associated with downregulation of PPAR-δ, UCP2 expression, upregulation of iNOS production, and increased oxidative/nitrotyrosine stress. These adverse effects of long-term high-salt diet were attenuated by chronic treatment with capsaicin. However, this effect of capsaicin was absent in TRPV1−/− mice on a high-salt diet. Our finding suggests that chronic dietary capsaicin consumption attenuates long-term high-salt diet-induced cardiac hypertrophy and fibrosis. This benefit effect is likely to be caused by TRPV1 mediated upregulation of PPAR-δ expression. Feng Gao, Yi Liang, Xiang Wang, Zongshi Lu, Li Li, Shanjun Zhu, Daoyan Liu, Zhencheng Yan, and Zhiming Zhu Copyright © 2014 Feng Gao et al. All rights reserved. PPARα: A Master Regulator of Bilirubin Homeostasis Wed, 23 Jul 2014 13:59:17 +0000 http://www.hindawi.com/journals/ppar/2014/747014/ Hypolipidemic fibrates activate the peroxisome proliferator-activated receptor (PPAR) α to modulate lipid oxidation and metabolism. The present study aimed at evaluating how 3 PPARα agonists, namely, fenofibrate, gemfibrozil, and Wy14,643, affect bilirubin synthesis and metabolism. Human umbilical vein epithelial cells (HUVEC) and coronary artery smooth muscle cells (CASMC) were cultured in the absence or presence of the 3 activators, and mRNA, protein, and/or activity levels of the bilirubin synthesizing heme oxygenase- (HO-) 1 and biliverdin reductase (BVR) enzymes were determined. Human hepatocytes (HH) and HepG2 cells sustained similar treatments, except that the expression of the bilirubin conjugating UDP-glucuronosyltransferase (UGT) 1A1 enzyme and multidrug resistance-associated protein (MRP) 2 transporter was analyzed. In HUVECs, gemfibrozil, fenofibrate, and Wy14,643 upregulated HO-1 mRNA expression without affecting BVR. Wy14,643 and fenofibrate also caused HO-1 protein accumulation, while gemfibrozil and fenofibrate favored the secretion of bilirubin in cell media. Similar positive regulations were also observed with the 3 PPARα ligands in CASMCs where HO-1 mRNA and protein levels were increased. In HH and HepG2 cells, both UGT1A1 and MRP2 transcripts were also accumulating. These observations indicate that PPARα ligands activate bilirubin synthesis in vascular cells and metabolism in liver cells. The clinical implications of these regulatory events are discussed. Cyril Bigo, Jenny Kaeding, Diala El Husseini, Iwona Rudkowska, Mélanie Verreault, Marie Claude Vohl, and Olivier Barbier Copyright © 2014 Cyril Bigo et al. All rights reserved. The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population Sun, 20 Jul 2014 12:17:44 +0000 http://www.hindawi.com/journals/ppar/2014/701971/ Peroxisome proliferator-activated receptor-γ (PPAR-γ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR) method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls ( for genotype; for allele). However, stratification by subtypes (sepsis, septic shock, and severe sepsis) revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls ( for allele and , for genotype). Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all ). In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all ). Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis. Guoda Ma, Haiyang Wang, Guixi Mo, Lili Cui, You Li, Yiming Shao, Xin Liu, Yuliu Xie, Jia Li, Jiawu Fu, Hua Tao, Bin Zhao, Liangqing Zhang, and Keshen Li Copyright © 2014 Guoda Ma et al. All rights reserved. 15-Deoxy-γ12,14-prostaglandin J2 Reduces Liver Impairment in a Model of ConA-Induced Acute Hepatic Inflammation by Activation of PPARγ and Reduction in NF-κB Activity Thu, 10 Jul 2014 09:45:07 +0000 http://www.hindawi.com/journals/ppar/2014/215631/ Objective. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) reduces inflammation and has been identified as an anti-inflammatory prostaglandin in numerous animal models. In this study, we investigated both effects of 15d-PGJ2 and its protection mechanism in concanavalin A- (ConA-) induced autoimmune hepatitis in mice. Materials and Methods. In vivo, Balb/C mice were injected with ConA (25 mg/kg) to induce acute autoimmune hepatitis, and 15d-PGJ2 (10 μg or 25 μg) was administered 1 h before the ConA injection. The histological grade, proinflammatory cytokine levels, and NF-κB and PPARγ activity were determined 6, 12, and 24 h after the ConA injection. In vitro, LO2 cells and RAW264.7 cells were pretreated with 15d-PGJ2 (2 μM) 1 h before the stimulation with ConA (30 μg/mL). The NF-κB and PPARγ activity were determined 30 min after the ConA administration. Results. Pretreatment with 15d-PGJ2 reduced the pathological effects of ConA-induced autoimmune hepatitis and significantly reduced the levels of cytokines after injection. 15d-PGJ2 activated PPARγ, blocked the degradation of IκBα, and inhibited the translocation of NF-κB into the nucleus. Conclusion. These results indicate that 15d-PGJ2 protects against ConA-induced autoimmune hepatitis by reducing proinflammatory cytokines. This reduction in inflammation may correlate with the activation of PPARγ and the reduction in NF-κB activity. Kan Chen, Jingjing Li, Junshan Wang, Yujing Xia, Weiqi Dai, Fan Wang, Miao Shen, Ping Cheng, Yan Zhang, Chengfen Wang, Jing Yang, Rong Zhu, Huawei Zhang, Yuanyuan Zheng, Jie Lu, Zhuoyi Fan, Yingqun Zhou, and Chuanyong Guo Copyright © 2014 Kan Chen et al. All rights reserved. Identification of Posttranslational Modifications in Peroxisome Proliferator-Activated Receptor γ Using Mass Spectrometry Wed, 25 Jun 2014 11:01:40 +0000 http://www.hindawi.com/journals/ppar/2014/468925/ Posttranslational modification (PTM) of proteins is critical for various cellular processes. However, there are few studies examining PTMs in specific proteins using unbiased approaches. Here we report the attempt to identify the PTMs in peroxisome proliferator-activated receptor γ (PPARγ) proteins using our previously established PTM analysis system. In this study, we identified several PTMs in exogenously expressed PPARγ2 proteins from 293T cells as well as endogenous PPARγ1 proteins from a Caco-2 colon cancer cell line. The identified PTMs include phosphorylation of serine 112 and serine 81 in PPARγ2 and PPARγ1, respectively, both of which are well-known mitogen-activated protein kinase- (MAP kinase-) mediated PTMs in PPARγ proteins, thus confirming our experimental approach. Furthermore, previously unknown PTMs were also identified, demonstrating that this method can be applied to find previously unidentified PTMs in PPARγ proteins and other proteins including nuclear receptors. Shogo Katsura, Tomoko Okumura, Ryo Ito, Akira Sugawara, and Atsushi Yokoyama Copyright © 2014 Shogo Katsura et al. All rights reserved. Correlation of Circulating Acid-Labile Subunit Levels with Insulin Sensitivity and Serum LDL Cholesterol in Patients with Type 2 Diabetes: Findings from a Prospective Study with Rosiglitazone Thu, 22 May 2014 12:19:07 +0000 http://www.hindawi.com/journals/ppar/2014/917823/ Silencing of acid-labile subunit (ALS) improved glucose metabolism in animal models. The aim of this study is to evaluate the effects of rosiglitazone (RSG) on ALS levels in individuals with type 2 diabetes. A randomized, double-blind, placebo-controlled trial was conducted. Subjects with type 2 diabetes mellitus were randomly distributed to an RSG-treated or a placebo group. Patients were evaluated prior to treatment at baseline and at 12 and 24 weeks after treatment. At baseline, ALS levels were negatively associated with low-density lipoprotein cholesterol (LDLc) levels and homeostatic model assessment version 2 insulin sensitivity (HOMA2-%S). Over 24 weeks, there was a significantly greater reduction in ALS levels in the nonobese RSG-treated individuals than placebo-treated group. The effect of RSG on ALS was not significant in obese individuals. Fasting plasma glucose and hemoglobin A1c were reduced, but total cholesterol and LDLc were increased, in patients on RSG. Change in ALS levels predicted changes in total cholesterol and HOMA2-%S over time. This study suggested a BMI-dependent effect of RSG treatment on ALS levels. Reduction of ALS by RSG increases the risk of atherosclerosis in individuals with type 2 diabetes. Ying-Chuen Lai, Hung-Yuan Li, Ta-Jen Wu, Chi-Yuan Jeng, and Lee-Ming Chuang Copyright © 2014 Ying-Chuen Lai et al. All rights reserved. Peroxisome Proliferator-Activated Receptor γ Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells Mon, 12 May 2014 06:58:13 +0000 http://www.hindawi.com/journals/ppar/2014/740121/ Lipid phosphate phosphohydrolase 1 (LPP1), a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor γ (PPARγ) in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs), quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) demonstrated that activation of PPARγ increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPARγ binds to the putative PPAR-responsive elements (PPREs) within the 5′-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPARγ and rosiglitazone, a specific ligand for PPARγ, could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPARγ transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPARγ in the metabolism of phospholipids. Yazi Huang, Beilei Zhao, Yahan Liu, and Nanping Wang Copyright © 2014 Yazi Huang et al. All rights reserved. Decrease of PPAR in Type-1-Like Diabetic Rat for Higher Mortality after Spinal Cord Injury Thu, 10 Apr 2014 14:04:02 +0000 http://www.hindawi.com/journals/ppar/2014/456386/ Changes in the peroxisome proliferator-activated receptors-δ (PPARδ) expression in rats after spinal cord injury (SCI) have been previously reported. Diabetic animals show a higher mortality after SCI. However, the relationship between the progress of diabetes and PPARδ in SCI remains unknown. In the present study, we used compressive SCI in streptozotocin-(STZ-) induced diabetic rats. GW0742, a PPARδ agonist, was used to evaluate its merit in STZ rats after SCI. Changes in PPARδ expression were detected by Western blot. Survival rates were also estimated. A lower expression of PPARδ in spinal cords of STZ-diabetic rats was observed. In addition, the survival times in two-week induction diabetes were longer than those in eight-week induction group, which is consistent with the expression of PPARδ in the spinal cord. Moreover, GW0742 significantly increased the survival time of STZ rats. Furthermore, their motor function and pain response were attenuated by GSK0660, a selective PPARδ antagonist, but were enhanced by GW0742. In conclusion, the data suggest that higher mortality rate in STZ-diabetic rats with SCI is associated with the decrease of PPARδ expression. Thus, change of PPARδ expression with the progress of diabetes seems responsible for the higher mortality rate after SCI. Cheng-Chia Tsai, Kung-Shing Lee, Sheng-Hsien Chen, Li-Jen Chen, Keng-Fan Liu, and Juei-Tang Cheng Copyright © 2014 Cheng-Chia Tsai et al. All rights reserved. Radix Astragali Improves Dysregulated Triglyceride Metabolism and Attenuates Macrophage Infiltration in Adipose Tissue in High-Fat Diet-Induced Obese Male Rats through Activating mTORC1-PPARγ Signaling Pathway Tue, 08 Apr 2014 09:55:51 +0000 http://www.hindawi.com/journals/ppar/2014/189085/ Increased levels of free fatty acids (FFAs) and hypertriglyceridemia are important risk factors for cardiovascular disease. The effective fraction isolated from radix astragali (RA) has been reported to alleviate hypertriglyceridemia. The mechanism of this triglyceride-lowering effect of RA is unclear. Here, we tested whether activation of the mTORC1-PPARγ signaling pathway is related to the triglyceride-lowering effect of RA. High-fat diet-induced obese (DIO) rats were fed a high-fat diet (40% calories from fat) for 9-10 weeks, and 4 g/kg/d RA was administered by gavage. RA treatment resulted in decreased fasting triglyceride levels, FFA concentrations, and adipocyte size. RA treated rats showed improved triglyceride clearance and fatty acid handling after olive oil overload. RA administration could also decrease macrophage infiltration and expression of MCP-1 and TNFα, but it may also increase the expression of PPARγ in epididymal adipose tissue from RA treated rats. Consistently, expressions of PPARγ and phospho-p70S6K were increased in differentiated 3T3-L1 adipocytes treated with RA. Moreover, RA couldnot upregulate the expression of PPARγ at the presence of rapamycin. In conclusion, the mTORC1-PPARγ signaling pathway is a potential mechanism through which RA exerts beneficial effects on the disturbance of triglyceride metabolism and dysfunction of adipose tissue in DIO rats. Yang Long, Xiang-Xun Zhang, Tao Chen, Yun Gao, and Hao-Ming Tian Copyright © 2014 Yang Long et al. All rights reserved. Peroxisome Proliferator Activator Receptor (PPAR)-γ Ligand, but Not PPAR-α, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver Wed, 02 Apr 2014 09:43:30 +0000 http://www.hindawi.com/journals/ppar/2014/626319/ Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy. Azza A. K. El-Sheikh and Rehab A. Rifaai Copyright © 2014 Azza A. K. El-Sheikh and Rehab A. Rifaai. All rights reserved. Effect of Chronic Valproic Acid Treatment on Hepatic Gene Expression Profile in Wfs1 Knockout Mouse Tue, 01 Apr 2014 11:38:11 +0000 http://www.hindawi.com/journals/ppar/2014/349525/ Valproic acid (VPA) is a widely used anticonvulsant and mood-stabilizing drug whose use is often associated with drug-induced weight gain. Treatment with VPA has been shown to upregulate Wfs1 expression in vitro. Aim of the present study was to compare the effect of chronic VPA treatment in wild type (WT) and Wfs1 knockout (KO) mice on hepatic gene expression profile. Wild type, Wfs1 heterozygous, and homozygous mice were treated with VPA for three months (300 mg/kg i.p. daily) and gene expression profiles in liver were evaluated using Affymetrix Mouse GeneChip 1.0 ST array. We identified 42 genes affected by Wfs1 genotype, 10 genes regulated by VPA treatment, and 9 genes whose regulation by VPA was dependent on genotype. Among the genes that were regulated differentially by VPA depending on genotype was peroxisome proliferator-activated receptor delta (Ppard), whose expression was upregulated in response to VPA treatment in WT, but not in Wfs1 KO mice. Thus, regulation of Ppard by VPA is dependent on Wfs1 genotype. Marite Punapart, Mall Eltermaa, Julia Oflijan, Silva Sütt, Anne Must, Sulev Kõks, Leonard C. Schalkwyk, Catherine Fernandes, Eero Vasar, Ursel Soomets, and Anton Terasmaa Copyright © 2014 Marite Punapart et al. All rights reserved. Effects and Potential Mechanisms of Pioglitazone on Lipid Metabolism in Obese Diabetic KKAy Mice Mon, 31 Mar 2014 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2014/538183/ This study aimed to analyze the effects and potential mechanisms of pioglitazone on triglyceride and cholesterol metabolism in obese diabetic KKAy mice. Pioglitazone was orally administered to KKAy mice over 30 days. Compared to C57BL/6J mice, KKAy mice developed obvious insulin resistance, hepatic steatosis, and hyperlipidemia. Pioglitazone treatment resulted in deteriorated microvesicular steatosis and elevated hepatic triglyceride levels, though plasma triglyceride and free fatty acid levels were reduced by the treatment, compared to nontreated KKAy mice. Plasma alanine aminotransferase activities were also significantly increased. Additionally, pioglitazone increased plasma concentrations of total cholesterol, HDL-cholesterol, and LDL-cholesterol but decreased hepatic cholesterol. Gene expression profiling revealed that pioglitazone stimulated hepatic peroxisome proliferator-activated receptor gamma hyperactivity, and induced the upregulation of adipocyte-specific and lipogenesis-related genes but downregulated of genes involved in triglyceride lipolysis and fatty acid β-oxidation. Pioglitazone also regulated the genes expression of hepatic cholesterol uptake and excretion, such as low density lipoprotein receptor (LDL-R) and scavenger receptor type-BI (SR-BI). These results suggested that pioglitazone could induce excessive hepatic triglyceride accumulation, thus aggravating liver steatosis and lesions in KKAy mice. Furthermore, pioglitazone may suppress the clearance of serum cholesterol from the liver predominantly through inhibition of LDL-R and SR-BI expression, thus increasing the plasma cholesterol. Jun Peng, Yi Huan, Qian Jiang, Su-juan Sun, Chun-ming Jia, and Zhu-fang Shen Copyright © 2014 Jun Peng et al. All rights reserved. PPARs and Metabolic Syndrome Mon, 24 Mar 2014 12:03:10 +0000 http://www.hindawi.com/journals/ppar/2014/832606/ Lihong Chen, Zhanjun Jia, and Guangrui Yang Copyright © 2014 Lihong Chen et al. All rights reserved. PPARG in Human Adipogenesis: Differential Contribution of Canonical Transcripts and Dominant Negative Isoforms Sun, 23 Mar 2014 07:58:28 +0000 http://www.hindawi.com/journals/ppar/2014/537865/ The nuclear receptor PPARγ is a key regulator of adipogenesis, and alterations of its function are associated with different pathological processes related to metabolic syndrome. We recently identified two PPARG transcripts encoding dominant negative PPARγ isoforms. The existence of different PPARG variants suggests that alternative splicing is crucial to modulate PPARγ function, underlying some underestimated aspects of its regulation. Here we investigate PPARG expression in different tissues and cells affected in metabolic syndrome and, in particular, during adipocyte differentiation of human mesenchymal stem cells. We defined the transcript-specific expression pattern of PPARG variants encoding both canonical and dominant negative isoforms and identified a novel PPARG transcript, γ1ORF4. Our analysis indicated that, during adipogenesis, the transcription of alternative PPARG variants is regulated in a time-specific manner through differential usage of distinct promoters. In addition, our analysis describes—for the first time—the differential contribution of three ORF4 variants to this process, suggesting a still unexplored role for these dominant negative isoforms during adipogenesis. Therefore, our results highlight crucial aspects of PPARG regulation, suggesting the need of further investigation to rule out the differential impact of all PPARG transcripts in both physiologic and pathologic conditions, such as metabolism-related disorders. M. Aprile, M. R. Ambrosio, V. D'Esposito, F. Beguinot, P. Formisano, V. Costa, and A. Ciccodicola Copyright © 2014 M. Aprile et al. All rights reserved. Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPARγ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease Tue, 18 Mar 2014 07:36:39 +0000 http://www.hindawi.com/journals/ppar/2014/432647/ Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPARγ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPARγ. Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPARγ-dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPARγ-mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPARγ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPARγ activation in hepatocytes and (ii) PPARγ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details. Merilin Al Sharif, Petko Alov, Vessela Vitcheva, Ilza Pajeva, and Ivanka Tsakovska Copyright © 2014 Merilin Al Sharif et al. All rights reserved. Synergistic Antiproliferative Effects of Combined γ-Tocotrienol and PPARγ Antagonist Treatment Are Mediated through PPARγ-Independent Mechanisms in Breast Cancer Cells Tue, 04 Mar 2014 09:47:35 +0000 http://www.hindawi.com/journals/ppar/2014/439146/ Previous findings showed that the anticancer effects of combined γ-tocotrienol and peroxisome proliferator activated receptor γ (PPARγ) antagonist treatment caused a large reduction in PPARγ expression. However, other studies suggest that the antiproliferative effects of γ-tocotrienol and/or PPARγ antagonists are mediated, at least in part, through PPARγ-independent mechanism(s). Studies were conducted to characterize the role of PPARγ in mediating the effects of combined treatment of γ-tocotrienol with PPARγ agonists or antagonists on the growth of PPARγ negative +SA mammary cells and PPARγ-positive and PPARγ-silenced MCF-7 and MDA-MB-231 breast cancer cells. Combined treatment of γ-tocotrienol with PPARγ antagonist decreased, while combined treatment of γ-tocotrienol with PPARγ agonist increased, growth of all cancer cells. However, treatment with high doses of 15d-PGJ2, an endogenous natural ligand for PPARγ, had no effect on cancer cell growth. Western blot and qRT-PCR studies showed that the growth inhibitory effects of combined γ-tocotrienol and PPARγ antagonist treatment decreased cyclooxygenase (COX-2), prostaglandin synthase (PGDS), and prostaglandin D2 (PGD2) synthesis. In conclusion, the anticancer effects of combined γ-tocotrienol and PPARγ antagonists treatment in PPARγ negative/silenced breast cancer cells are mediated through PPARγ-independent mechanisms that are associated with a downregulation in COX-2, PGDS, and PGD2 synthesis. Abhita Malaviya and Paul W. Sylvester Copyright © 2014 Abhita Malaviya and Paul W. Sylvester. All rights reserved. PPAR-γ Regulates Trophoblast Differentiation in the BeWo Cell Model Sun, 23 Feb 2014 12:54:49 +0000 http://www.hindawi.com/journals/ppar/2014/637251/ Common pregnancy complications, such as severe preeclampsia and intrauterine growth restriction, disrupt pregnancy progression and impair maternal and fetal wellbeing. Placentas from such pregnancies exhibit lesions principally within the syncytiotrophoblast (SCT), a layer in direct contact with maternal blood. In humans and mice, glial cell missing-1 (GCM-1) promotes differentiation of underlying cytotrophoblast cells into the outer SCT layer. GCM-1 may be regulated by the transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-γ); in mice, PPAR-γ promotes labyrinthine trophoblast differentiation via Gcm-1, and, as we previously demonstrated, PPAR-γ activation ameliorates disease features in rat model of preeclampsia. Here, we aimed to characterize the baseline activity of PPAR-γ in the human choriocarcinoma BeWo cell line that mimics SCT formation in vitro and modulate PPAR-γ activity to study its effects on cell proliferation versus differentiation. We report a novel negative autoregulatory mechanism between PPAR-γ activity and expression and show that blocking PPAR-γ activity induces cell proliferation at the expense of differentiation, while these remain unaltered following treatment with the agonist rosiglitazone. Gaining a deeper understanding of the role and activity of PPAR-γ in placental physiology will offer new avenues for the development of secondary prevention and/or treatment options for placentally-mediated pregnancy complications. Khrystyna Levytska, Sascha Drewlo, Dora Baczyk, and John Kingdom Copyright © 2014 Khrystyna Levytska et al. All rights reserved. PPARs Integrate the Mammalian Clock and Energy Metabolism Wed, 19 Feb 2014 12:52:13 +0000 http://www.hindawi.com/journals/ppar/2014/653017/ Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPARα and PPARγ are direct regulators of core clock components, Bmal1 and Rev-erbα, and, conversely, PPARα is also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation. Lihong Chen and Guangrui Yang Copyright © 2014 Lihong Chen and Guangrui Yang. All rights reserved. Neuroprotective Potential of Peroxisome Proliferator Activated Receptor-α Agonist in Cognitive Impairment in Parkinson’s Disease: Behavioral, Biochemical, and PBPK Profile Wed, 19 Feb 2014 08:07:12 +0000 http://www.hindawi.com/journals/ppar/2014/753587/ Parkinson’s disease (PD) is a common neurodegenerative disorder affecting 1% of the population by the age of 65 years and 4-5% of the population by the age of 85 years. PD affects functional capabilities of the patient by producing motor symptoms and nonmotor symptoms. Apart from this, it is also associated with a higher risk of cognitive impairment that may lead to memory loss, confusion, and decreased attention span. In this study, we have investigated the effect of fenofibrate, a PPAR-α agonist in cognitive impairment model in PD. Bilateral intranigral administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (100 µg/1 µL/side) produced significant cognitive dysfunctions. Fenofibrate treatment at 10, 30, and 100 mg/kg for twenty-five days was found to be neuroprotective and improved cognitive impairment in MPTP-induced PD model as evident from behavioral, biochemical (MDA, GSH, TNF-α, and IL-6), immunohistochemistry (TH), and DNA fragmentation (TUNEL positive cells) studies. Further, physiologically based pharmacokinetic (PBPK) modeling study was performed using GastroPlus to characterize the kinetics of fenofibric acid in the brain. A good agreement was found between pharmacokinetic parameters obtained from the actual and simulated plasma concentration-time profiles of fenofibric acid. Results of this study suggest that PPAR-α agonist (fenofibrate) is neuroprotective in PD-induced cognitive impairment. Dedeepya Uppalapati, Nihar R. Das, Rahul P. Gangwal, Mangesh V. Damre, Abhay T. Sangamwar, and Shyam S. Sharma Copyright © 2014 Dedeepya Uppalapati et al. All rights reserved. Rosiglitazone Attenuated Endothelin-1-Induced Vasoconstriction of Pulmonary Arteries in the Rat Model of Pulmonary Arterial Hypertension via Differential Regulation of ET-1 Receptors Tue, 18 Feb 2014 11:49:53 +0000 http://www.hindawi.com/journals/ppar/2014/374075/ Pulmonary arterial hypertension (PAH) is a fatal disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. Activation of the endothelin (ET)-1 system has been demonstrated in plasma and lung tissue of PAH patients as well as in animal models of PAH. Recently, peroxisome proliferator-activated receptor γ (PPARγ) agonists have been shown to ameliorate PAH. The present study aimed to investigate the mechanism for the antivasoconstrictive effects of rosiglitazone in response to ET-1 in PAH. Sprague-Dawley rats were exposed to chronic hypoxia (10% oxygen) for 3 weeks. Pulmonary arteries from PAH rats showed an enhanced vasoconstriction in response to ET-1. Treatment with PPARγ agonist rosiglitazone (20 mg/kg per day) with oral gavage for 3 days attenuated the vasocontractive effect of ET-1. The effect of rosiglitazone was lost in the presence of -NAME, indicating a nitric oxide-dependent mechanism. Western blotting revealed that rosiglitazone increased but decreased level in pulmonary arteries from PAH rats. antagonist A192621 diminished the effect of rosiglitazone on ET-1-induced contraction. These results demonstrated that rosiglitazone attenuated ET-1-induced pulmonary vasoconstriction in PAH through differential regulation of the subtypes of ET-1 receptors and, thus, provided a new mechanism for the therapeutic use of PPARγ agonists in PAH. Yahan Liu, Xiao Yu Tian, Yu Huang, and Nanping Wang Copyright © 2014 Yahan Liu et al. All rights reserved. New Insights into the PPARγ Agonists for the Treatment of Diabetic Nephropathy Wed, 29 Jan 2014 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2014/818530/ Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPARγ agonists involving the endogenous PPARγ ligands and selective PPARγ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPARγ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPARγ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPARγ agonists were fully addressed. Zhanjun Jia, Ying Sun, Guangrui Yang, Aihua Zhang, Songming Huang, Kristina Marie Heiney, and Yue Zhang Copyright © 2014 Zhanjun Jia et al. All rights reserved. The Rate of Decline of Glomerular Filtration Rate May Not Be Associated with Polymorphism of the PPAR2 Gene in Patients with Type 1 Diabetes and Nephropathy Wed, 22 Jan 2014 14:28:44 +0000 http://www.hindawi.com/journals/ppar/2014/523584/ The aim of the study was to investigate whether a Pro12Ala polymorphism in the peroxisome proliferator-activated receptor gamma 2 (PPARγ2) gene is associated with the progress of diabetic nephropathy in patients with type 1 diabetes. 197 Caucasian patients with type 1 diabetes and ethnically matched 151 normal healthy controls were genotyped for this polymorphism. Results showed that there were no significant differences in the frequencies of the genotypes and alleles of the polymorphism between groups. Multiple regression analysis in 77 patients demonstrated that the rate of decline in renal function in terms of glomerular filtration rate was significantly correlated to the baseline level of cholesterol (), mean diastolic blood pressure during follow-up period (), and baseline level of HbA1c () adjusting for the effect of diabetes duration and gender, but no significant association was found between the polymorphism and the progression of diabetic nephropathy in our studied population. In summary, our results show that the PPARγ2 polymorphism is unlikely to be associated with the development and progression of the diabetic nephropathy in patients with type 1 diabetes. Further studies in different populations may be warranted to confirm our findings as the sample size in our study was relatively small. Bingmei Yang, Hongxin Zhao, Beverley Ann Millward, and Andrew Glen Demaine Copyright © 2014 Bingmei Yang et al. All rights reserved. The Proatherogenic Effect of Chronic Nitric Oxide Synthesis Inhibition in ApoE-Null Mice Is Dependent on the Presence of PPARα Wed, 22 Jan 2014 11:11:27 +0000 http://www.hindawi.com/journals/ppar/2014/124583/ Inhibition of endothelial nitric oxide synthase (eNOS) accelerates atherosclerosis in ApoE-null mice by impairing the balance between angiotensin II (AII) and NO. Our previous data suggested a role for PPARα in the deleterious effect of the renin-angiotensin system (RAS). We tested the hypothesis that ApoE-null mice lacking PPARα (DKO mice) would be resistant to the proatherogenic effect of NOS inhibition. DKO mice fed a Western diet were immune to the 23% worsening in aortic sinus plaque area seen in the ApoE-null animals under 12 weeks of NOS inhibition with a subpressor dose of L-NAME, . This was accompanied by a doubling of reactive oxygen species (ROS-) generating aortic NADPH oxidase activity (a target of AII, which paralleled Nox1 expression) and by a 10-fold excess of the proatherogenic iNOS, . L-NAME also caused a doubling of aortic renin and angiotensinogen mRNA level in the ApoE-null mice but not in the DKO, and it upregulated eNOS in the DKO mice only. These data suggest that, in the ApoE-null mouse, PPARα contributes to the proatherogenic effect of unopposed RAS/AII action induced by L-NAME, an effect which is associated with Nox1 and iNOS induction, and is independent of blood pressure and serum lipids. Michal Vechoropoulos, Maya Ish-Shalom, Sigal Shaklai, Jessica Sack, Naftali Stern, and Karen M. Tordjman Copyright © 2014 Michal Vechoropoulos et al. All rights reserved. HMGB1 Is Involved in the Protective Effect of the PPARα Agonist Fenofibrate against Cardiac Hypertrophy Thu, 09 Jan 2014 11:39:24 +0000 http://www.hindawi.com/journals/ppar/2014/541394/ High mobility group box 1 (HMGB1) is a ubiquitous nuclear DNA-binding protein whose function is dependent on its cellular location. Extracellular HMGB1 is regarded as a delayed mediator of proinflammatory cytokines for initiating and amplifying inflammatory responses, whereas nuclear HMGB1 has been found to prevent cardiac hypertrophy and heart failure. Because fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, has shown both protective effects against cardiac hypertrophy and inhibitory effects against inflammation, the potential modulation of HMGB1 expression and secretion by fenofibrate is of great interest. We herein provide evidence that fenofibrate modulates basal and LPS-stimulated HMGB1 expression and localization in addition to secretion of HMGB1 in cardiomyocytes. In addition, administration of fenofibrate to mice prevented the development of cardiac hypertrophy induced by thoracic transverse aortic constriction (TAC) while increasing levels of nuclear HMGB1. Altogether, these data suggest that fenofibrate may inhibit the development of cardiac hypertrophy by regulating HMGB1 expression, which provides a new potential strategy to treat cardiac hypertrophy. Zhankui Jia, Rui Xue, Gangqiong Liu, Ling Li, Jinjian Yang, Guofu Pi, Shengli Ma, and Quancheng Kan Copyright © 2014 Zhankui Jia et al. All rights reserved. PPAR Agonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice Mon, 30 Dec 2013 11:32:33 +0000 http://www.hindawi.com/journals/ppar/2013/612971/ Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR)γ and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15-hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPARγ activation on renal mPGES-1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN. Ying Sun, Zhanjun Jia, Gang Liu, Li Zhou, Mi Liu, Baoxue Yang, and Tianxin Yang Copyright © 2013 Ying Sun et al. All rights reserved. Effects of PPARγ Agonist Pioglitazone on Redox-Sensitive Cellular Signaling in Young Spontaneously Hypertensive Rats Thu, 19 Dec 2013 15:28:31 +0000 http://www.hindawi.com/journals/ppar/2013/541871/ PPARγ receptor plays an important role in oxidative stress response. Its agonists can influence vascular contractility in experimental hypertension. Our study was focused on the effects of a PPARγ agonist pioglitazone (PIO) on blood pressure regulation, vasoactivity of vessels, and redox-sensitive signaling at the central (brainstem, BS) and peripheral (left ventricle, LV) levels in young prehypertensive rats. 5-week-old SHR were treated either with PIO (10 mg/kg/day, 2 weeks) or with saline using gastric gavage. Administration of PIO significantly slowed down blood pressure increase and improved lipid profile and aortic relaxation after insulin stimulation. A significant increase in PPARγ expression was found only in BS, not in LV. PIO treatment did not influence NOS changes, but had tissue-dependent effect on SOD regulation and increased SOD activity, observed in LV. The treatment with PIO differentially affected also the levels of other intracellular signaling components: Akt kinase increased in the the BS, while β-catenin level was down-regulated in the BS and up-regulated in the LV. We found that the lowering of blood pressure in young SHR can be connected with insulin sensitivity of vessels and that β-catenin and SOD levels are important agents mediating PIO effects in the BS and LV. Ima Dovinová, Miroslav Barancik, Miroslava Majzunova, Stefan Zorad, Lucia Gajdosechová, Linda Gresová, Sona Cacanyiova, Frantisek Kristek, Peter Balis, and Julie Y. H. Chan Copyright © 2013 Ima Dovinová et al. All rights reserved. Pseudoginsenoside F11, a Novel Partial PPARγ Agonist, Promotes Adiponectin Oligomerization and Secretion in 3T3-L1 Adipocytes Wed, 18 Dec 2013 10:51:13 +0000 http://www.hindawi.com/journals/ppar/2013/701017/ PPARγ is a nuclear hormone receptor that functions as a master regulator of adipocyte differentiation and development. Full PPARγ agonists, such as the thiazolidinediones (TZDs), have been widely used to treat type 2 diabetes. However, they are characterized by undesirable side effects due to their strong agonist activities. Pseudoginsenoside F11 (p-F11) is an ocotillol-type ginsenoside isolated from Panax quinquefolium L. (American ginseng). In this study, we found that p-F11 activates PPARγ with modest adipogenic activity. In addition, p-F11 promotes adiponectin oligomerization and secretion in 3T3-L1 adipocytes. We also found that p-F11 inhibits obesity-linked phosphorylation of PPARγ at Ser-273 by Cdk5. Therefore, p-F11 is a novel partial PPARγ agonist, which might have the potential to be developed as a new PPARγ-targeted therapeutics for type 2 diabetes. Guoyu Wu, Junyang Yi, Ling Liu, Pengcheng Wang, Zhijie Zhang, and Zhen Li Copyright © 2013 Guoyu Wu et al. All rights reserved. PPARgamma-Dependent Control of Renin Expression: Molecular Mechanisms and Pathophysiological Relevance Wed, 30 Oct 2013 12:03:26 +0000 http://www.hindawi.com/journals/ppar/2013/451016/ During the last years accumulating evidence demonstrated that the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) regulates the expression of renin gene and thus the overall renin production. This review summarizes the current knowledge of the transcriptional control of the renin gene by PPARgamma received from variety of models ranging from cell culture to transgenic animals. The molecular mechanisms of the PPARgamma action on renin are particularly interesting because they are featured by two newly described characteristics: one of them is the recently identified PPARgamma target sequence Pal3 which is specific for the human renin gene and mediates exceptionally high sensitivity to transactivation; the other is the potentiating effect of PPARgamma on the cAMP signaling in the renin-producing cells. Furthermore, I discuss the need for generating of additional transgenic animal models which are more appropriate with regard to the role of the PPARgamma-dependent regulation of the renin gene expression in human diseases such as arterial hypertension and metabolic syndrome. Vladimir T. Todorov Copyright © 2013 Vladimir T. Todorov. All rights reserved. The PPARα/γ Agonist, Tesaglitazar, Improves Insulin Mediated Switching of Tissue Glucose and Free Fatty Acid Utilization In Vivo in the Obese Zucker Rat Sun, 27 Oct 2013 09:13:23 +0000 http://www.hindawi.com/journals/ppar/2013/305347/ Metabolic flexibility was assessed in male Zucker rats: lean controls, obese controls, and obese rats treated with the dual peroxisome proliferator activated receptor (PPAR) agonist, tesaglitazar, 3 μmol/kg/day for 3 weeks. Whole body glucose disposal rate () and hepatic glucose output (HGO) were assessed under basal fasting and hyperinsulinemic isoglycemic clamp conditions using [3,3H]glucose. Indices of tissue specific glucose utilization () were measured at basal, physiological, and supraphysiological levels of insulinemia using 2-deoxy-D-[2,6-3H]glucose. Finally, whole body and tissue specific FFA and glucose utilization and metabolic fate were evaluated under basal and hyperinsulinemic conditions using a combination of [U-13C]glucose, 2-deoxy-D-[U-14C]glucose, [U-14C]palmitate, and [9,10-3H]-(R)-bromopalmitate. Tesaglitazar improved whole body insulin action by greater suppression of HGO and stimulation of compared to obese controls. This involved increased insulin stimulation of in fat and skeletal muscle as well as increased glycogen synthesis. Tesaglitazar dramatically improved insulin mediated suppression of plasma FFA level, whole body turnover (), and muscle, liver, and fat utilization. At basal insulin levels, tesaglitazar failed to lower HGO or compared to obese controls. In conclusion, the results demonstrate that tesaglitazar has a remarkable ability to improve insulin mediated control of glucose and FFA fluxes in obese Zucker rats. Kristina Wallenius, Ann Kjellstedt, Pia Thalén, Lars Löfgren, and Nicholas D. Oakes Copyright © 2013 Kristina Wallenius et al. All rights reserved. Polymorphisms in PPAR Genes (PPARD, PPARG, and PPARGC1A) and the Risk of Chronic Kidney Disease in Japanese: Cross-Sectional Data from the J-MICC Study Sun, 27 Oct 2013 08:53:11 +0000 http://www.hindawi.com/journals/ppar/2013/980471/ Chronic kidney disease (CKD) is well known as a strong risk factor for both end stage renal disease and cardiovascular disease. To clarify the association of polymorphisms in the PPAR genes (PPARD, PPARG, and PPARGC1A) with the risk of CKD in Japanese, we examined this association among the Japanese subjects using the cross-sectional data of J-MICC (Japan Multi-Institutional Collaborative Cohort) Study. The subjects for this analysis were 3,285 men and women, aged 35–69 years, selected from J-MICC Study participants; genotyping was conducted by multiplex polymerase chain reaction-based Invader assay. The prevalence of CKD was determined for CKD stages 3–5 (defined as eGFR < 60 ml/min/1.73 m2). Participants with CKD accounted for 17.3% of the study population. When those with PPARD T-842C T/T were defined as reference, those with PPARD T-842C T/C and C/C demonstrated the OR for CKD of 1.26 (95%CI 1.04–1.53) and 1.31 (95%CI 0.83–2.06), respectively. There were no significant associations between the polymorphisms in other PPAR genes and the risk of CKD. The present study found a significantly increased risk of CKD in those with the C allele of PPARD T-842C, which may suggest the possibility of personalized risk estimation of this life-limiting disease in the near future. Asahi Hishida, Kenji Wakai, Mariko Naito, Takashi Tamura, Sayo Kawai, Nobuyuki Hamajima, Isao Oze, Takeshi Imaizumi, Tanvir Chowdhury Turin, Sadao Suzuki, Motahare Kheradmand, Haruo Mikami, Keizo Ohnaka, Yoshiyuki Watanabe, Kokichi Arisawa, Michiaki Kubo, and Hideo Tanaka Copyright © 2013 Asahi Hishida et al. All rights reserved.