PPAR Research http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2015 , Hindawi Publishing Corporation . All rights reserved. KLF15 and PPARα Cooperate to Regulate Cardiomyocyte Lipid Gene Expression and Oxidation Thu, 26 Feb 2015 09:22:25 +0000 http://www.hindawi.com/journals/ppar/2015/201625/ The metabolic myocardium is an omnivore and utilizes various carbon substrates to meet its energetic demand. While the adult heart preferentially consumes fatty acids (FAs) over carbohydrates, myocardial fuel plasticity is essential for organismal survival. This metabolic plasticity governing fuel utilization is under robust transcriptional control and studies over the past decade have illuminated members of the nuclear receptor family of factors (e.g., PPARα) as important regulators of myocardial lipid metabolism. However, given the complexity of myocardial metabolism in health and disease, it is likely that other molecular pathways are likely operative and elucidation of such pathways may provide the foundation for novel therapeutic approaches. We previously demonstrated that Kruppel-like factor 15 (KLF15) is an independent regulator of cardiac lipid metabolism thus raising the possibility that KLF15 and PPARα operate in a coordinated fashion to regulate myocardial gene expression requisite for lipid oxidation. In the current study, we show that KLF15 binds to, cooperates with, and is required for the induction of canonical PPARα-mediated gene expression and lipid oxidation in cardiomyocytes. As such, this study establishes a molecular module involving KLF15 and PPARα and provides fundamental insights into the molecular regulation of cardiac lipid metabolism. Domenick A. Prosdocimo, Jenine E. John, Lilei Zhang, Elizabeth S. Efraim, Rongli Zhang, Xudong Liao, and Mukesh K. Jain Copyright © 2015 Domenick A. Prosdocimo et al. All rights reserved. Retracted: A Role for PPARγ in the Regulation of Cytokines in Immune Cells and Cancer Mon, 02 Feb 2015 07:13:19 +0000 http://www.hindawi.com/journals/ppar/2015/982750/ PPAR Research Copyright © 2015 PPAR Research. All rights reserved. Peroxisome Proliferator-Activated Receptor-γ in Thyroid Autoimmunity Sun, 01 Feb 2015 10:04:47 +0000 http://www.hindawi.com/journals/ppar/2015/232818/ Peroxisome proliferator-activated receptor- (PPAR-) γ expression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO), such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif) receptor 3 (CXCR3) and cognate chemokines (C-X-C motif) ligand (CXCL)9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γ agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of thyroid autoimmune disorders. Silvia Martina Ferrari, Poupak Fallahi, Roberto Vita, Alessandro Antonelli, and Salvatore Benvenga Copyright © 2015 Silvia Martina Ferrari et al. All rights reserved. Therapeutic Effects of PPARα on Neuronal Death and Microvascular Impairment Thu, 29 Jan 2015 07:58:22 +0000 http://www.hindawi.com/journals/ppar/2015/595426/ Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARα has potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα’s effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARα agonist in diabetic microvascular complications. Elizabeth P. Moran and Jian-xing Ma Copyright © 2015 Elizabeth P. Moran and Jian-xing Ma. All rights reserved. PGC1α −1 Nucleosome Position and Splice Variant Expression and Cardiovascular Disease Risk in Overweight and Obese Individuals Sun, 28 Dec 2014 00:10:15 +0000 http://www.hindawi.com/journals/ppar/2014/895734/ PGC1, a transcriptional coactivator, interacts with PPARs and others to regulate skeletal muscle metabolism. PGC1 undergoes splicing to produce several mRNA variants, with the NTPGC1 variant having a similar biological function to the full length PGC1 (FLPGC1). CVD is associated with obesity and T2D and a lower percentage of type 1 oxidative fibers and impaired mitochondrial function in skeletal muscle, characteristics determined by PGC1 expression. PGC1 expression is epigenetically regulated in skeletal muscle to determine mitochondrial adaptations, and epigenetic modifications may regulate mRNA splicing. We report in this paper that skeletal muscle PGC1  −1 nucleosome (−1N) position is associated with splice variant NTPGC1 but not FLPGC1 expression. Division of participants based on the −1N position revealed that those individuals with a −1N phased further upstream from the transcriptional start site (UP) expressed lower levels of NTPGC1 than those with the −1N more proximal to TSS (DN). UP showed an increase in body fat percentage and serum total and LDL cholesterol. These findings suggest that the −1N may be a potential epigenetic regulator of NTPGC1 splice variant expression, and −1N position and NTPGC1 variant expression in skeletal muscle are linked to CVD risk. This trial is registered with clinicaltrials.gov, identifier NCT00458133. Tara M. Henagan, Laura K. Stewart, Laura A. Forney, Lauren M. Sparks, Neil Johannsen, and Timothy S. Church Copyright © 2014 Tara M. Henagan et al. All rights reserved. Erratum to “15-Deoxy-12,14-prostaglandin J2 Reduces Liver Impairment in a Model of ConA-Induced Acute Hepatic Inflammation by Activation of PPAR and Reduction in NF-B Activity” Thu, 20 Nov 2014 00:00:00 +0000 http://www.hindawi.com/journals/ppar/2014/864839/ 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. The Antifibrosis Effects of Peroxisome Proliferator-Activated Receptor δ on Rat Corneal Wound Healing after Excimer Laser Keratectomy Thu, 13 Nov 2014 09:28:21 +0000 http://www.hindawi.com/journals/ppar/2014/464935/ Corneal stromal fibrosis characterized by myofibroblasts and abnormal extracellular matrix (ECM) is usually the result of inappropriate wound healing. The present study tested the hypothesis that the ligand activation of peroxisome proliferator-activated receptor (PPAR) δ had antifibrosis effects in a rat model of corneal damage. Adult Sprague-Dawley rats underwent bilateral phototherapeutic keratectomy (PTK). The eyes were randomized into four groups: PBS, GW501516 (a selective agonist of PPARδ), GSK3787 (a selective antagonist of PPARδ), or GW501516 combined with GSK3787. The agents were subconjunctivally administered twice a week until sacrifice. The cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and postmortem histology. A myofibroblast marker (α-smooth muscle actin) and ECM production (fibronectin, collagen type III and collagen type I) were examined by immunohistochemistry and RT-PCR. At the early stages of wound healing, GW501516 inhibited reepithelialization and promoted angiogenesis. During the remodeling phase of wound healing, GW501516 attenuated the activation and proliferation of keratocytes, which could be reversed by GSK3787. GW501516 decreased transdifferentiation from keratocytes into myofibroblasts, ECM synthesis, and corneal haze. These results demonstrate that GW501516 controls corneal fibrosis and suggest that PPARδ may potentially serve as a therapeutic target for treating corneal scars. Yun Gu, Xuan Li, Tiangeng He, Zhixin Jiang, Peng Hao, and Xin Tang Copyright © 2014 Yun Gu et al. All rights reserved. The Impact of Chronic Kidney Disease and Short-Term Treatment with Rosiglitazone on Plasma Cell-Free DNA Levels Mon, 13 Oct 2014 11:40:54 +0000 http://www.hindawi.com/journals/ppar/2014/643189/ Patients with chronic kidney disease (CKD) are at increased risk of cardiovascular disease. Circulating free nucleic acids, known as cell-free DNA (cfDNA), have been proposed as a novel biomarker of cardiovascular risk. The impact of renal impairment on cfDNA levels and whether cfDNA is associated with endothelial dysfunction and inflammation in CKD has not been systematically studied. We analysed cfDNA concentrations from patients with varying degrees of CKD. In addition, to determine whether there is a relationship between cfDNA, inflammation, and endothelial dysfunction in CKD, levels of proinflammatory cytokines and von Willebrand Factor (vWF) were measured in patients treated with the peroxisome proliferator-activated receptor gamma agonist rosiglitazone or placebo for 8 weeks. cfDNA levels were not increased with renal impairment or associated with the degree of renal dysfunction . Treatment with rosiglitazone for 8 weeks, but not placebo, was more likely to lead to a reduction in cfDNA levels ; however, the absolute changes in cfDNA concentrations during treatment were not statistically significant . cfDNA levels correlated with markers of endothelial dysfunction (hsCRP ) and vWF . In conclusion, cell-free DNA levels are not influenced by renal impairment but do reflect endothelial dysfunction in patients with CKD. Amanda L. McGuire, Nadia Urosevic, Doris T. Chan, Gursharan Dogra, Timothy J. J. Inglis, and Aron Chakera Copyright © 2014 Amanda L. McGuire et al. All rights reserved. The Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene Modifies the Association of Physical Activity and Body Mass Changes in Polish Women Mon, 13 Oct 2014 08:09:26 +0000 http://www.hindawi.com/journals/ppar/2014/373782/ Peroxisome proliferator-activated receptor 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. Aleksandra Zarebska, Zbigniew Jastrzebski, Pawel Cieszczyk, Agata Leonska-Duniec, Katarzyna Kotarska, Mariusz Kaczmarczyk, Marek Sawczuk, and Agnieszka Maciejewska-Karlowska Copyright © 2014 Aleksandra Zarebska et al. All rights reserved. PPAR Gamma Expression Levels during Development of Heart Failure in Patients with Coronary Artery Disease after Coronary Artery Bypass-Grafting Mon, 13 Oct 2014 07:19:29 +0000 http://www.hindawi.com/journals/ppar/2014/242790/ Genetic research has elucidated molecular mechanisms of heart failure (HF). Peroxisome proliferator-activated receptors (PPARs) seem to be important in etiology of HF. The aim of study was to find the correlation between PPAR expression during development of HF in patients and coronary artery disease (CAD) after coronary artery bypass-grafting (CABG). Methods and Results. We followed up 157 patients (mean age 63) with CAD without clinical, laboratory, or echo parameters of HF who underwent CABG. Clinical and laboratory status were assessed before CABG and at 1, 12, and 24 months. During CABG slices of aorta (Ao) and LV were collected for genetic research. HF was defined as LVEF <40% or NT-proBNP >400 pg/mL or 6MWT <400 m. Patients were divided into 2 groups: with and without HF. PPAR expression in Ao and LV was not increased in both groups at 2-year follow-up. Sensitivity of PPAR expression in Ao above 1.1075 in detection of HF was 20.5% (AUC 0.531, 95% CI 0.442–0.619). Positive predictive value (Ppv) was 85.7%. Sensitivity and specificity of PPAR expression in the LV in detection of HF were 58% and 92.9%, respectively (AUC 0.540, 95% CI 0.452–0.626). Ppv was 73.2%. Conclusion. PPAR expression in Ao and LV was comparable and should not be used as predictive factor for development of HF in patients with CAD after CABG. Izabela Wojtkowska, Andrzej Tysarowski, Katarzyna Seliga, Janusz A. Siedlecki, Zbigniew Juraszyński, Milosz Marona, Lidia Greszata, Anna Skrobisz, Karol Kaminski, Robert Sawicki, and Janina Stępińska Copyright © 2014 Izabela Wojtkowska et al. All rights reserved. Dietary Conjugated Linoleic Acid Supplementation Leads to Downregulation of PPAR Transcription in Broiler Chickens and Reduction of Adipocyte Cellularity Thu, 18 Sep 2014 08:08:15 +0000 http://www.hindawi.com/journals/ppar/2014/137652/ Conjugated linoleic acids (CLA) act as an important ligand for nuclear receptors in adipogenesis and fat deposition in mammals and avian species. This study aimed to determine whether similar effects are plausible on avian abdominal fat adipocyte size, as well as abdominal adipogenic transcriptional level. CLA was supplemented at different levels, namely, (i) basal diet without CLA (5% palm oil) (CON), (ii) basal diet with 2.5% CLA and 2.5% palm oil (LCLA), and (iii) basal diet with 5% CLA (HCLA).The content of cis-9, trans-11 CLA was between 1.69- and 2.3-fold greater () than that of trans-10, cis-12 CLA in the abdominal fat of the LCLA and HCLA group. The adipogenic capacity of the abdominal fat depot in LCLA and HCLA fed chicken is associated with a decreased proportion of adipose cells and monounsaturated fatty acids (MUFA). The transcriptional level of adipocyte protein (aP2) and peroxisome proliferator-activated receptor gamma (PPARγ) was downregulated by 1.08- to 2.5-fold in CLA supplemented diets, respectively. It was speculated that feeding CLA to broiler chickens reduced adipocyte size and downregulated PPARγ and aP2 that control adipocyte cellularity. Elevation of CLA isomers into their adipose tissue provides a potential CLA-rich source for human consumption. Suriya Kumari Ramiah, Goh Yong Meng, Tan Sheau Wei, Yeap Swee Keong, and Mahdi Ebrahimi Copyright © 2014 Suriya Kumari Ramiah et al. All rights reserved. Role of PPARγ in the Differentiation and Function of Neurons Tue, 26 Aug 2014 08:46:46 +0000 http://www.hindawi.com/journals/ppar/2014/768594/ Neuronal processes (neurites and axons) have an important role in brain cells communication and, generally, they are damaged in neurodegenerative diseases. Recent evidence has showed that the activation of PPARγ pathway promoted neuronal differentiation and axon polarity. In addition, activation of PPARγ using thiazolidinediones (TZDs) prevented neurodegeneration by reducing neuronal death, improving mitochondrial function, and decreasing neuroinflammation in neuropathic pain. In this review, we will discuss important evidence that supports a possible role of PPARγ in neuronal development, improvement of neuronal health, and pain signaling. Therefore, activation of PPARγ is a potential target with therapeutic applications against neurodegenerative disorders, brain injury, and pain regulation. Rodrigo A. Quintanilla, Elias Utreras, and Fabián A. Cabezas-Opazo Copyright © 2014 Rodrigo A. Quintanilla et al. 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.