PPAR Research http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . All rights reserved. Pioglitazone Effect on Glioma Stem Cell Lines: Really a Promising Drug Therapy for Glioblastoma? Wed, 25 May 2016 11:26:05 +0000 http://www.hindawi.com/journals/ppar/2016/7175067/ Glioblastoma multiforme (GBM) represents one of the most frequent malignant brain tumors. Current therapies do not provide real solutions to this pathology. Their failure can be ascribed to a cell subpopulation with stem-like properties called glioma stem cells (GSCs). Therefore, new therapeutic strategies GSC-targeted are needed. PPARγ, a nuclear receptor involved in lipid metabolism, has already been indicated as a promising target for antineoplastic therapies. Recent studies have reported that synthetic PPARγ agonists, already in clinical use for the treatment of type II diabetes, exhibit antineoplastic effects in a wide range of malignant tumor cells, including glioma cells. We investigated the effect of the synthetic PPARγ agonist Pioglitazone on viability, proliferation, morphology, and differentiation in six GSC lines isolated from GBM patients. We also analyzed Pioglitazone-induced changes in transcriptional levels of Wnt/β catenin related genes. Results showed that response to Pioglitazone was heterogeneous inducing an evident decrease of cell viability and proliferation only in a subset of GSC lines. We did not find any sign of cell differentiation neither observing cell morphology nor analyzing the expression of stemness and differentiation markers. Moreover, Wnt/β signaling pathway was only mildly affected from a transcriptional point of view after Pioglitazone exposure. Chiara Cilibrasi, Valentina Butta, Gabriele Riva, and Angela Bentivegna Copyright © 2016 Chiara Cilibrasi et al. All rights reserved. Current Advances in the Biochemical and Physiological Aspects of the Treatment of Type 2 Diabetes Mellitus with Thiazolidinediones Mon, 23 May 2016 06:25:28 +0000 http://www.hindawi.com/journals/ppar/2016/7614270/ The present review summarizes the current advances in the biochemical and physiological aspects in the treatment of type 2 diabetes mellitus (DM2) with thiazolidinediones (TZDs). DM2 is a metabolic disorder characterized by hyperglycemia, triggering the abnormal activation of physiological pathways such as glucose autooxidation, polyol’s pathway, formation of advance glycation end (AGE) products, and glycolysis, leading to the overproduction of reactive oxygen species (ROS) and proinflammatory cytokines, which are responsible for the micro- and macrovascular complications of the disease. The treatment of DM2 has been directed toward the reduction of hyperglycemia using different drugs such as insulin sensitizers, as the case of TZDs, which are able to lower blood glucose levels and circulating triglycerides by binding to the nuclear peroxisome proliferator-activated receptor gamma (PPARγ) as full agonists. When TZDs interact with PPARγ, the receptor regulates the transcription of different genes involved in glucose homeostasis, insulin resistance, and adipogenesis. However, TZDs exhibit some adverse effects such as fluid retention, weight gain, hepatotoxicity, plasma-volume expansion, hemodilution, edema, bone fractures, and congestive heart failure, which limits their use in DM2 patients. D. Alemán-González-Duhart, F. Tamay-Cach, S. Álvarez-Almazán, and J. E. Mendieta-Wejebe Copyright © 2016 D. Alemán-González-Duhart et al. All rights reserved. Peroxisome Proliferator-Activated Receptor-γ Is Critical to Cardiac Fibrosis Thu, 12 May 2016 17:12:45 +0000 http://www.hindawi.com/journals/ppar/2016/2198645/ Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily, which plays a central role in regulating lipid and glucose metabolism. However, accumulating evidence demonstrates that PPARγ agonists have potential to reduce inflammation, influence the balance of immune cells, suppress oxidative stress, and improve endothelial function, which are all involved in the cellular and molecular mechanisms of cardiac fibrosis. Thus, in this review we discuss the role of PPARγ in various cardiovascular conditions associated with cardiac fibrosis, including diabetes mellitus, hypertension, myocardial infarction, heart failure, ischemia/reperfusion injury, atrial fibrillation, and several other cardiovascular disease (CVD) conditions, and summarize the developmental status of PPARγ agonists for the clinical management of CVD. Huang-Jun Liu, Hai-Han Liao, Zheng Yang, and Qi-Zhu Tang Copyright © 2016 Huang-Jun Liu et al. All rights reserved. 15-Deoxy-Δ12,14-prostaglandin J2 Induces Apoptosis and Upregulates SOCS3 in Human Thyroid Cancer Cells Sun, 17 Apr 2016 12:14:31 +0000 http://www.hindawi.com/journals/ppar/2016/4106297/ The cyclopentenone prostaglandin 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is a natural ligand of peroxisome proliferator-activated receptor gamma (PPAR-γ) and a potential mediator of apoptosis in cancer cells. In the present study, we evaluated the effect of 15d-PGJ2 in human thyroid papillary carcinoma cells (TPC-1) using different doses of 15d-PGJ2 (0.6 to 20 μM) to determine IC50 (9.3 μM) via the MTT assay. The supernatant culture medium of the TPC-1 cells that was treated either with 15d-PGJ2 or with vehicle (control) for 24 hours was assessed for IL-6 secretion via CBA assay. RT-qPCR was used to evaluate mRNA expression of IL-6, SOCS1, SOCS3, and STAT3. TPC-1 cells treated with 15d-PGJ2 decreased the secretion and expression of IL-6 and STAT3, while it increased SOCS1 and SOCS3. Overall, we demonstrated that 15d-PGJ2 downregulated IL-6 signaling pathway and led TPC-1 cells into apoptosis. In conclusion, 15d-PGJ2 shows the potential to become a new therapeutic approach for thyroid tumors. Carlos Antônio Trindade-da-Silva, Carolina Fernandes Reis, Lara Vecchi, Marcelo Henrique Napimoga, Marcelo Sperandio, Bruna França Matias Colombo, Patrícia Terra Alves, Laura Sterian Ward, Carlos Ueira-Vieira, and Luiz Ricardo Goulart Copyright © 2016 Carlos Antônio Trindade-da-Silva et al. All rights reserved. Timcodar (VX-853) Is a Non-FKBP12 Binding Macrolide Derivative That Inhibits PPARγ and Suppresses Adipogenesis Thu, 14 Apr 2016 09:47:09 +0000 http://www.hindawi.com/journals/ppar/2016/6218637/ Nutrient overload and genetic factors have led to a worldwide epidemic of obesity that is the underlying cause of diabetes, atherosclerosis, and cardiovascular disease. In this study, we used macrolide drugs such as FK506, rapamycin, and macrolide derived, timcodar (VX-853), to determine their effects on lipid accumulation during adipogenesis. Rapamycin and FK506 bind to FK506-binding proteins (FKBPs), such as FKBP12, which causes suppression of the immune system and inhibition of mTOR. Rapamycin has been previously reported to inhibit the adipogenic process and lipid accumulation. However, rapamycin treatment in rodents caused immune suppression and glucose resistance, even though the mice lost weight. Here we show that timcodar (1 μM), a non-FKBP12-binding drug, significantly () inhibited lipid accumulation during adipogenesis. A comparison of the same concentration of timcodar (1 μM) and rapamycin (1 μM) showed that both are inhibitors of lipid accumulation during adipogenesis. Importantly, timcodar potently () suppressed transcriptional regulators of adipogenesis, PPARγ and C/EBPα, resulting in the inhibition of genes involved in lipid accumulation. These studies set the stage for timcodar as a possible antiobesity therapy, which is rapidly emerging as a pandemic. Terry D. Hinds Jr., Kezia John, Lucien McBeth, Christopher J. Trabbic, and Edwin R. Sanchez Copyright © 2016 Terry D. Hinds Jr. et al. All rights reserved. PPARgene: A Database of Experimentally Verified and Computationally Predicted PPAR Target Genes Mon, 11 Apr 2016 09:41:25 +0000 http://www.hindawi.com/journals/ppar/2016/6042162/ The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear receptor superfamily. Upon ligand binding, PPARs activate target gene transcription and regulate a variety of important physiological processes such as lipid metabolism, inflammation, and wound healing. Here, we describe the first database of PPAR target genes, PPARgene. Among the 225 experimentally verified PPAR target genes, 83 are for PPARα, 83 are for PPARβ/δ, and 104 are for PPARγ. Detailed information including tissue types, species, and reference PubMed IDs was also provided. In addition, we developed a machine learning method to predict novel PPAR target genes by integrating in silico PPAR-responsive element (PPRE) analysis with high throughput gene expression data. Fivefold cross validation showed that the performance of this prediction method was significantly improved compared to the in silico PPRE analysis method. The prediction tool is also implemented in the PPARgene database. Li Fang, Man Zhang, Yanhui Li, Yan Liu, Qinghua Cui, and Nanping Wang Copyright © 2016 Li Fang et al. All rights reserved. Pioglitazone Protected against Cardiac Hypertrophy via Inhibiting AKT/GSK3β and MAPK Signaling Pathways Sun, 27 Mar 2016 11:52:39 +0000 http://www.hindawi.com/journals/ppar/2016/9174190/ Peroxisome proliferator activated receptor γ (PPARγ) has been closely involved in the process of cardiovascular diseases. This study was to investigate whether pioglitazone (PIO), a PPARγ agonist, could protect against pressure overload-induced cardiac hypertrophy. Mice were orally given PIO (2.5 mg/kg) from 1 week after aortic banding and continuing for 7 weeks. The morphological examination and biochemical analysis were used to evaluate the effects of PIO. Neonatal rat ventricular cardiomyocytes were also used to verify the protection of PIO against hypertrophy in vitro. The results in our study demonstrated that PIO remarkably inhibited hypertrophic response induced by aortic banding in vivo. Besides, PIO also suppressed cardiac fibrosis in vivo. PIO treatment also inhibited the activation of protein kinase B (AKT)/glycogen synthase kinase-3β (GSK3β) and mitogen-activated protein kinase (MAPK) in the heart. In addition, PIO alleviated angiotensin II-induced hypertrophic response in vitro. In conclusion, PIO could inhibit cardiac hypertrophy via attenuation of AKT/GSK3β and MAPK pathways. Wen-Ying Wei, Zhen-Guo Ma, Si-Chi Xu, Ning Zhang, and Qi-Zhu Tang Copyright © 2016 Wen-Ying Wei et al. All rights reserved. Fenofibrate plus Metformin Produces Cardioprotection in a Type 2 Diabetes and Acute Myocardial Infarction Model Wed, 16 Mar 2016 10:00:10 +0000 http://www.hindawi.com/journals/ppar/2016/8237264/ We investigated whether fenofibrate, metformin, and their combination generate cardioprotection in a rat model of type 2 diabetes (T2D) and acute myocardial infarction (AMI). Streptozotocin-induced diabetic- (DB-) rats received 14 days of either vehicle, fenofibrate, metformin, or their combination and immediately after underwent myocardial ischemia/reperfusion (I/R). Fenofibrate plus metformin generated cardioprotection in a DBI/R model, reported as decreased coronary vascular resistance, compared to DBI/R-Vehicle, smaller infarct size, and increased cardiac work. The subchronic treatment with fenofibrate plus metformin increased, compared with DBI/R-Vehicle, total antioxidant capacity, manganese-dependent superoxide dismutase activity (MnSOD), guanosine triphosphate cyclohydrolase I (GTPCH-I) expression, tetrahydrobiopterin : dihydrobiopterin (BH4 : BH2) ratio, endothelial nitric oxide synthase (eNOS) activity, nitric oxide (NO) bioavailability, and decreased inducible NOS (iNOS) activity. These findings suggest that PPARα activation by fenofibrate + metformin, at low doses, generates cardioprotection in a rat model of T2D and AMI and may represent a novel treatment strategy to limit I/R injury in patients with T2D. Víctor Hugo Oidor-Chan, Enrique Hong, Francisca Pérez-Severiano, Sergio Montes, Juan Carlos Torres-Narváez, Leonardo del Valle-Mondragón, Gustavo Pastelín-Hernández, and Alicia Sánchez-Mendoza Copyright © 2016 Víctor Hugo Oidor-Chan et al. All rights reserved. Possible Role of Interaction between PPARα and Cyclophilin D in Cardioprotection of AMPK against In Vivo Ischemia-Reperfusion in Rats Tue, 08 Mar 2016 06:12:42 +0000 http://www.hindawi.com/journals/ppar/2016/9282087/ Activated AMPK protects the heart from cardiac ischemia-reperfusion (IR) injury and is associated with inhibition of mitochondrial permeability transition pore (PTP) opening. On the other hand, pharmacological inhibition of the PTP reduces infarct size and improves cardiac function. However, it is unclear whether beneficial effects of AMPK are mediated through the PTP and, if they are not, whether simultaneous activation of AMPK and inhibition of the PTP exert synergistic protective effects against cardiac IR injury. Here, we examined the effects of the AMPK activator, A-769662 in combination with the PTP inhibitor, sanglifehrin A (SfA) on in vivo cardiac IR. Cardiac dysfunction following IR injury was associated with decreased activity of the mitochondrial electron transport chain (ETC) and increased mitochondrial ROS and PTP opening. Administration of A-769662 or SfA individually upon reperfusion improved cardiac function, reduced infarction size, and inhibited ROS production and PTP opening. However, simultaneous administration of SfA and A-769662 did not provide synergistic improvement of postischemic recovery of cardiac and mitochondrial function, though both compounds disrupted IR-induced interaction between PPARα and CyP-D. In conclusion, A-769662 or SfA prevents PPARα interaction with CyP-D, improving cardiac outcomes and increasing mitochondrial function, and simultaneous administration of the drugs does not provide synergistic effects. Giselle Barreto-Torres and Sabzali Javadov Copyright © 2016 Giselle Barreto-Torres and Sabzali Javadov. All rights reserved. Inducible Conditional Vascular-Specific Overexpression of Peroxisome Proliferator-Activated Receptor Beta/Delta Leads to Rapid Cardiac Hypertrophy Thu, 03 Mar 2016 11:48:03 +0000 http://www.hindawi.com/journals/ppar/2016/7631085/ Peroxisome proliferator-activated receptors are nuclear receptors which function as ligand-activated transcription factors. Among them, peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in the heart and thought to have cardioprotective functions due to its beneficial effects in metabolic syndrome. As we already showed that PPARβ/δ activation resulted in an enhanced cardiac angiogenesis and growth without impairment of heart function, we were interested to determine the effects of a specific activation of PPARβ/δ in the vasculature on cardiac performance under normal and in chronic ischemic heart disease conditions. We analyzed the effects of a specific PPARβ/δ overexpression in endothelial cells on the heart using an inducible conditional vascular-specific mouse model. We demonstrate that vessel-specific overexpression of PPARβ/δ induces rapid cardiac angiogenesis and growth with an increase in cardiomyocyte size. Upon myocardial infarction, vascular overexpression of PPARβ/δ, despite the enhanced cardiac vessel formation, does not protect against chronic ischemic injury. Our results suggest that the proper balance of PPARβ/δ activation in the different cardiac cell types is required to obtain beneficial effects on the outcome in chronic ischemic heart disease. Kay-Dietrich Wagner, Ana Vukolic, Delphine Baudouy, Jean-François Michiels, and Nicole Wagner Copyright © 2016 Kay-Dietrich Wagner et al. All rights reserved. PPARα Agonist Fenofibrate Reduced the Secreting Load of β-Cells in Hypertriglyceridemia Patients with Normal Glucose Tolerance Mon, 29 Feb 2016 08:00:35 +0000 http://www.hindawi.com/journals/ppar/2016/6232036/ Hypertriglyceridemia is an important risk factor associated with insulin resistance and β-cell dysfunction. This study investigated the effects of hypertriglyceridemia and fenofibrate treatment on insulin sensitivity and β-cell function in subjects with normal glucose tolerance. A total of 1974 subjects with normal glucose tolerance were divided into the normal TG group (NTG group, ) and hypertriglyceridemia group (HTG group, ). Next, 92 patients selected randomly from 672 patients with hypertriglyceridemia were assigned to a 24-week fenofibrate treatment. The HTG group had increased waist circumference (WC), body mass index (BMI), homeostasis model assessment of insulin resistance (HOMA-IR), and homeostasis model assessment of β-cell function (HOMA-β) and decreased high-density lipoprotein cholesterol (HDL-C) compared with the NTG group (all ). The 24-week fenofibrate treatment significantly decreased the WC, BMI, TG, HOMA-IR, and HOMA-β levels and increased the HDL-C levels in the patients with hypertriglyceridemia (WC, BMI, and HOMA-IR: ; TG, HDL-C, and HOMA-β: ). The fenofibrate treatment significantly alleviated insulin resistance and reduced the secreting load of β-cells in the hypertriglyceridemia patients with normal glucose tolerance. Jia Liu, Rui Lu, Ying Wang, Yanjin Hu, Yumei Jia, Ning Yang, Jing Fu, and Guang Wang Copyright © 2016 Jia Liu et al. All rights reserved. Differential Roles of Peroxisome Proliferator-Activated Receptor-α and Receptor-γ on Renal Crystal Formation in Hyperoxaluric Rodents Sun, 28 Feb 2016 11:32:04 +0000 http://www.hindawi.com/journals/ppar/2016/9605890/ Peroxisome proliferator-activated receptors (PPARs) and related inflammatory and oxidative molecule expression were investigated in a hyperoxaluric rodent model to evaluate the in vivo efficacy of PPAR agonists in preventing renal crystal formation. PPAR expression was examined in a mouse hyperoxaluria kidney stone model induced by daily intra-abdominal glyoxylate injection. Therapeutic effects of the PPARα agonist fenofibrate and PPARγ agonist pioglitazone were also assessed in a 1% ethylene glycol-induced rat model of hyperoxaluria. Crystal formation, inflammation, cell injury, apoptosis, and oxidative stress were compared to those of vehicle-treated controls. Quantitative reverse transcription-polymerase chain reaction revealed that PPARα and PPARγ expression decrease and increase, respectively, during crystal formation in hyperoxaluric kidneys. In addition, PPARα localized to the cytoplasm of both proximal and distal tubular cells, whereas PPARγ accumulated in the nucleus of proximal tubular cells. Furthermore, renal crystal formation was significantly less prevalent in pioglitazone-treated rats but higher in the fenofibrate-treated and fenofibrate/pioglitazone-cotreated groups compared to controls, thus indicating that pioglitazone, but not fenofibrate, markedly decreased cell inflammation, oxidative stress, and apoptosis. Collectively, the results demonstrated that PPARγ suppressed renal crystal formation via its antioxidative and anti-inflammatory effects; however, the renotoxicity of PPARα may elicit the opposite effect. Kazumi Taguchi, Atsushi Okada, Shuzo Hamamoto, Rei Unno, Takahiro Kobayashi, Ryosuke Ando, Keiichi Tozawa, Bing Gao, Kenjiro Kohri, and Takahiro Yasui Copyright © 2016 Kazumi Taguchi et al. All rights reserved. The Correlation of PPARα Activity and Cardiomyocyte Metabolism and Structure in Idiopathic Dilated Cardiomyopathy during Heart Failure Progression Mon, 15 Feb 2016 12:14:31 +0000 http://www.hindawi.com/journals/ppar/2016/7508026/ This study aimed to define relationship between PPAR expression and metabolic-structural characteristics during HF progression in hearts with DCM phenotype. Tissue endomyocardial biopsy samples divided into three groups according to LVEF ((I) 45–50%, ; (II) 30–40%, ; (III) <30%, ; and control (donor hearts, >60%, )) were investigated. The PPAR mRNA expression in the failing hearts was low in Group (I), high in Group (II), and comparable to that of the control in Group (III). There were analogous changes in the expression of FAT/CD36 and CPT-1 mRNA in contrast to continuous overexpression of GLUT-4 mRNA and significant increase of PDK-4 mRNA in Group (II). In addition, significant structural changes of cardiomyocytes with glycogen accumulation were accompanied by increased expression of PPAR. For the entire study population with HF levels of FAT/CD36 mRNA showed a strong tendency of negative correlation with LVEF. In conclusion, PPAR elevated levels may be a direct cause of adverse remodeling, both metabolic and structural. Thus, there is limited time window for therapy modulating cardiac metabolism and protecting cardiomyocyte structure in failing heart. E. Czarnowska, D. Domal-Kwiatkowska, E. Reichman-Warmusz, J. B. Bierla, A. Sowinska, A. Ratajska, K. Goral-Radziszewska, and R. Wojnicz Copyright © 2016 E. Czarnowska et al. All rights reserved. Polymorphisms of the PPAR-γ (rs1801282) and Its Coactivator (rs8192673) Have a Minor Effect on Markers of Carotid Atherosclerosis in Patients with Type 2 Diabetes Mellitus Tue, 02 Feb 2016 08:40:02 +0000 http://www.hindawi.com/journals/ppar/2016/4934251/ Background. The present study was designed to clarify whether common single nucleotide polymorphisms (SNPs) of the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ) gene (rs1801282) and the Peroxisome Proliferator-Activated Receptor-γ Coactivator-1 (PGC-1α) gene (rs8192673) are associated with markers of carotid and coronary atherosclerosis in Caucasians with type 2 diabetes mellitus (T2DM). Patients and Methods. 595 T2DM subjects and 200 control subjects were enrolled in the cross-sectional study. Markers of carotid atherosclerosis were assessed ultrasonographically. In 215 out of 595 subjects with T2DM, a coronary computed tomography angiography (CCTA) was performed for diagnostic purposes. Genotyping of either rs1801282 or rs8192673 was performed using KASPar assays. Results. In our study, we demonstrated an effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM in univariate and in multivariable linear regression analyses. Finally, we did not demonstrate any association between either rs1801282 or rs8192673 and markers of coronary atherosclerosis. Conclusions. In our study, we demonstrated a minor effect of the rs1801282 on markers of carotid atherosclerosis (presence of plaques) in Caucasians with T2DM. Moreover, we demonstrated a minor effect of the rs8192673 on CIMT progression in the 3.8-year follow-up in Caucasians with T2DM. Aleš Pleskovič, Marija Šantl Letonja, Andreja Cokan Vujkovac, Jovana Nikolajević Starćević, and Danijel Petrovič Copyright © 2016 Aleš Pleskovič et al. All rights reserved. Caffeic Acid Phenethyl Ester Regulates PPAR’s Levels in Stem Cells-Derived Adipocytes Sun, 24 Jan 2016 09:19:14 +0000 http://www.hindawi.com/journals/ppar/2016/7359521/ Hypertrophic obesity inhibits activation of peroxisome proliferators-activated receptor gamma (PPARγ), considered the key mediator of the fully differentiated and insulin sensitive adipocyte phenotype. We examined the effects of Caffeic Acid Phenethyl Ester (Cape), isolated from propolis, a honeybee hive product, on Adipose Stem Cells (ASCs) differentiation to the adipocyte lineage. Finally we tested the effects of Cape on insulin-resistant adipocytes. Quantification of Oil Red O-stained cells showed that lipid droplets decreased following Cape treatment as well as radical oxygen species formation. Additionally, exposure of ASC to high glucose levels decreased adiponectin and increased proinflammatory cytokines mRNA levels, which were reversed by Cape-mediated increase of insulin sensitivity. Cape treatment resulted in decreased triglycerides synthesis and increased beta-oxidation. Exposure of ASCs to Lipopolysaccharide (LPS) induced a reduction of PPARγ, an increase of IL-6 levels associated with a well-known stimulation of lipolysis; Cape partially attenuated the LPS-mediated effects. These observations reveal the main role of PPARγ in the adipocyte function and during ASC differentiation. As there is now substantial interest in functional food and nutraceutical products, the observed therapeutic value of Cape in insulin-resistance related diseases should be taken into consideration. Luca Vanella, Daniele Tibullo, Justyna Godos, Francesca Romana Pluchinotta, Claudia Di Giacomo, Valeria Sorrenti, Rosaria Acquaviva, Alessandra Russo, Giovanni Li Volti, and Ignazio Barbagallo Copyright © 2016 Luca Vanella et al. All rights reserved. Smad2/3 Upregulates the Expression of Vimentin and Affects Its Distribution in DBP-Exposed Sertoli Cells Thu, 24 Dec 2015 14:21:06 +0000 http://www.hindawi.com/journals/ppar/2015/489314/ Sertoli cells (SCs) in the testes provide physical and nutritional support to germ cells. The vimentin cytoskeleton in SCs is disrupted by dibutyl phthalate (DBP), which leads to SCs dysfunction. In a previous study, we found that peroxisome proliferator-activated receptor alpha (PPARα) influenced the distribution of vimentin by affecting its phosphorylation in DBP-exposed SCs. In the present study, we investigated the role of Smad2/3 in regulating the expression of vimentin in DBP-exposed SCs. We hypothesized that Smad2/3 affects the distribution of vimentin by regulating its expression and that there is cross talk between Smad2/3 and PPARα. The real-time PCR and ChIP-qPCR results showed that SB431542 (an inhibitor of Smad2/3) could significantly attenuate the expression of vimentin induced by DBP in SCs. Phosphorylated and soluble vimentin were both downregulated by SB431542 pretreatment. WY14643 (an agonist of PPARα) pretreatment stimulated, while GW6471 (an antagonist of PPARα) inhibited, the activity of Smad2/3; SB431542 pretreatment also inhibited the activity of PPARα, but it did not rescue the DBP-induced collapse in vimentin. Our results suggest that, in addition to promoting the phosphorylation of vimentin, DBP also stimulates the expression of vimentin by activating Smad2/3 in SCs and thereby induces irregular vimentin distribution. Xi Zhang, Xiaogang Wang, Taixiu Liu, Min Mo, Lin Ao, Jinyi Liu, Jia Cao, and Zhihong Cui Copyright © 2015 Xi Zhang et al. All rights reserved. PPARs: Protectors or Opponents of Myocardial Function? Wed, 02 Dec 2015 14:22:00 +0000 http://www.hindawi.com/journals/ppar/2015/835985/ Over 5 million people in the United States suffer from the complications of heart failure (HF), which is a rapidly expanding health complication. Disorders that contribute to HF include ischemic cardiac disease, cardiomyopathies, and hypertension. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family. There are three PPAR isoforms: PPARα, PPARγ, and PPARδ. They can be activated by endogenous ligands, such as fatty acids, as well as by pharmacologic agents. Activators of PPARs are used for treating several metabolic complications, such as diabetes and hyperlipidemia that are directly or indirectly associated with HF. However, some of these drugs have adverse effects that compromise cardiac function. This review article aims to summarize the current basic and clinical research findings of the beneficial or detrimental effects of PPAR biology on myocardial function. Christine J. Pol, Melissa Lieu, and Konstantinos Drosatos Copyright © 2015 Christine J. Pol et al. All rights reserved. PPARγ and the Innate Immune System Mediate the Resolution of Inflammation Wed, 02 Dec 2015 07:29:41 +0000 http://www.hindawi.com/journals/ppar/2015/549691/ The resolution of inflammation is an active and dynamic process, mediated in large part by the innate immune system. Resolution represents not only an increase in anti-inflammatory actions, but also a paradigm shift in immune cell function to restore homeostasis. PPARγ, a ligand activated transcription factor, has long been studied for its anti-inflammatory actions, but an emerging body of literature is investigating the role of PPARγ and its ligands (including thiazolidinediones, prostaglandins, and oleanolic acids) in all phases of resolution. PPARγ can shift production from pro- to anti-inflammatory mediators by neutrophils, platelets, and macrophages. PPARγ and its ligands further modulate platelet and neutrophil function, decreasing trafficking, promoting neutrophil apoptosis, and preventing platelet-leukocyte interactions. PPARγ alters macrophage trafficking, increases efferocytosis and phagocytosis, and promotes alternative M2 macrophage activation. There are also roles for this receptor in the adaptive immune response, particularly regarding B cells. These effects contribute towards the attenuation of multiple disease states, including COPD, colitis, Alzheimer’s disease, and obesity in animal models. Finally, novel specialized proresolving mediators—eicosanoids with critical roles in resolution—may act through PPARγ modulation to promote resolution, providing another exciting area of therapeutic potential for this receptor. Amanda Croasdell, Parker F. Duffney, Nina Kim, Shannon H. Lacy, Patricia J. Sime, and Richard P. Phipps Copyright © 2015 Amanda Croasdell et al. All rights reserved. Zebrafish as a Model to Study the Role of Peroxisome Proliferating-Activated Receptors in Adipogenesis and Obesity Mon, 30 Nov 2015 11:51:20 +0000 http://www.hindawi.com/journals/ppar/2015/358029/ The Peroxisome Proliferator-Activated Receptors (PPARs) PPARA and PPARD are regulators of lipid metabolism with important roles in energy release through lipid breakdown, while PPARG plays a key role in lipid storage and adipogenesis. The aim of this review is to describe the role of PPARs in lipid metabolism, adipogenesis, and obesity and evaluate the zebrafish as an emerging vertebrate model to study the function of PPARs. Zebrafish are an appropriate model to study human diseases, including obesity and related metabolic diseases, as pathways important for adipogenesis and lipid metabolism which are conserved between mammals and fish. This review synthesizes knowledge on the role of PPARs in zebrafish and focuses on the putative function of PPARs in zebrafish adipogenesis. Using in silico analysis, we confirm the presence of five PPARs (pparaa, pparab, pparda, ppardb, and pparg) in the zebrafish genome with 67–74% identity to human and mouse PPARs. During development, pparda/b paralogs and pparg show mRNA expression around the swim bladder and pancreas, the region where adipocytes first develop, whereas pparg is detectable in adipocytes at 15 days post fertilization (dpf). This review indicates that the zebrafish is a promising model to investigate the specific functions of PPARs in adipogenesis and obesity. Marjo J. Den Broeder, Victoria A. Kopylova, Leonie M. Kamminga, and Juliette Legler Copyright © 2015 Marjo J. Den Broeder et al. All rights reserved. PPAR-α Agonist Fenofibrate Decreased Serum Irisin Levels in Type 2 Diabetes Patients with Hypertriglyceridemia Thu, 26 Nov 2015 14:21:54 +0000 http://www.hindawi.com/journals/ppar/2015/924131/ Irisin is related to insulin resistance and metabolic disorders. The physiologic effects of irisin are partially mediated through peroxisome proliferator-activated receptor-α (PPAR-α). We investigated the effect of fenofibrate, a PPAR-α agonist, on serum irisin in type 2 diabetes patients with hypertriglyceridemia. This study evaluated cross-sectional and interventional studies of 25 type 2 diabetes patients with hypertriglyceridemia (group A) and 40 controls (group B). Group A was treated with fenofibrate (200 mg/day) for 8 weeks. Serum irisin and clinical characteristics were examined. Serum irisin was significantly higher in group A compared with group B ( versus  ng/ml, ) and correlated with body mass index (, ), fasting blood glucose (, ), total cholesterol (, ), and high-density lipoprotein cholesterol (, ). In multiple regression analysis after controlling for confounders, only fasting blood glucose (, ) and high-density lipoprotein cholesterol (, ) were independently related to serum irisin. After 8 weeks of fenofibrate treatment, serum irisin significantly decreased in group A compared with baseline ( versus  ng/ml, ). Conclusively, fenofibrate decreased serum irisin in type 2 diabetes patients with hypertriglyceridemia, indicating that PPAR-α agonists may protect against metabolic disorders by improving irisin resistance. Xiaomeng Feng, Xia Gao, Yumei Jia, Heng Zhang, Qingrong Pan, Zhi Yao, Ning Yang, Jia Liu, Yuan Xu, Guang Wang, and Xinchun Yang Copyright © 2015 Xiaomeng Feng et al. All rights reserved. Treatment with PPARα Agonist Clofibrate Inhibits the Transcription and Activation of SREBPs and Reduces Triglyceride and Cholesterol Levels in Liver of Broiler Chickens Wed, 25 Nov 2015 09:07:30 +0000 http://www.hindawi.com/journals/ppar/2015/347245/ PPARα agonist clofibrate reduces cholesterol and fatty acid concentrations in rodent liver by an inhibition of SREBP-dependent gene expression. In present study we investigated the regulation mechanisms of the triglyceride- and cholesterol-lowering effect of the PPARα agonist clofibrate in broiler chickens. We observed that PPARα agonist clofibrate decreases the mRNA and protein levels of LXRα and the mRNA and both precursor and nuclear protein levels of SREBP1 and SREBP2 as well as the mRNA levels of the SREBP1 (FASN and GPAM) and SREBP2 (HMGCR and LDLR) target genes in the liver of treated broiler chickens compared to control group, whereas the mRNA level of INSIG2, which inhibits SREBP activation, was increased in the liver of treated broiler chickens compared to control group. Taken together, the effects of PPARα agonist clofibrate on lipid metabolism in liver of broiler chickens involve inhibiting transcription and activation of SREBPs and SREBP-dependent lipogenic and cholesterologenic gene expression, thereby resulting in a reduction of the triglyceride and cholesterol levels in liver of broiler chickens. Lijun Zhang, Chunyan Li, Fang Wang, Shenghua Zhou, Mingjun Shangguan, Lina Xue, Bianying Zhang, Fuxiang Ding, Dequan Hui, Aihua Liang, and Dongchang He Copyright © 2015 Lijun Zhang et al. All rights reserved. AICAR Protects against High Palmitate/High Insulin-Induced Intramyocellular Lipid Accumulation and Insulin Resistance in HL-1 Cardiac Cells by Inducing PPAR-Target Gene Expression Mon, 16 Nov 2015 14:13:16 +0000 http://www.hindawi.com/journals/ppar/2015/785783/ Here we studied the impact of 5-aminoimidazole-4-carboxamide riboside (AICAR), a well-known AMPK activator, on cardiac metabolic adaptation. AMPK activation by AICAR was confirmed by increased phospho-Thr172-AMPK and phospho-Ser79-ACC protein levels in HL-1 cardiomyocytes. Then, cells were exposed to AICAR stimulation for 24 h in the presence or absence of the AMPK inhibitor Compound C, and the mRNA levels of the three PPARs were analyzed by real-time RT-PCR. Treatment with AICAR induced gene expression of all three PPARs, but only the Ppara and Pparg regulation were dependent on AMPK. Next, we exposed HL-1 cells to high palmitate/high insulin (HP/HI) conditions either in presence or in absence of AICAR, and we evaluated the expression of selected PPAR-targets genes. HP/HI induced insulin resistance and lipid storage was accompanied by increased Cd36, Acot1, and Ucp3 mRNA levels. AICAR treatment induced the expression of Acadvl and Glut4, which correlated to prevention of the HP/HI-induced intramyocellular lipid build-up, and attenuation of the HP/HI-induced impairment of glucose uptake. These data support the hypothesis that AICAR contributes to cardiac metabolic adaptation via regulation of transcriptional mechanisms. Ricardo Rodríguez-Calvo, Manuel Vázquez-Carrera, Luis Masana, and Dietbert Neumann Copyright © 2015 Ricardo Rodríguez-Calvo et al. All rights reserved. Restoration of Endothelial Function in Pparα−/− Mice by Tempol Sun, 15 Nov 2015 13:27:51 +0000 http://www.hindawi.com/journals/ppar/2015/728494/ Peroxisome proliferator activated receptor alpha (PPARα) is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARα is present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARα contributes to endothelial function, conduit and cerebral resistance arteries were studied in Pparα−/− mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2α and constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT) and Pparα−/−; however, relaxation/dilation to acetylcholine (ACh) was impaired. There was no difference in relaxation between WT and Pparα−/− aorta to treatment with a nitric oxide (NO) surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced in Pparα−/− aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS) scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation in Pparα−/− mice. These results suggest that Pparα−/− mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARα receptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease. Neerupma Silswal, Nikhil Parelkar, Jon Andresen, and Michael J. Wacker Copyright © 2015 Neerupma Silswal et al. All rights reserved. PPARα Is Required for PPARδ Action in Regulation of Body Weight and Hepatic Steatosis in Mice Thu, 29 Oct 2015 07:45:11 +0000 http://www.hindawi.com/journals/ppar/2015/927057/ Peroxisome proliferator activated receptors alpha (PPARα) and delta (PPARδ) belong to the nuclear receptor superfamily. PPARα is a target of well established lipid-lowering drugs. PPARδ (also known as PPARβ/δ) has been investigated as a promising antidiabetic drug target; however, the evidence in the literature on PPARδ effect on hepatic lipid metabolism is inconsistent. Mice conditionally expressing human PPARδ demonstrated pronounced weight loss and promoted hepatic steatosis when treated with GW501516 (PPARδ-agonist) when compared to wild type mice. This effect was completely absent in mice with either a dominant negative form of PPARδ or deletion of the DNA binding domain of PPARδ. This confirmed the absolute requirement for PPARδ in the physiological actions of GW501516 and confirmed the potential utility against the human form of this receptor. Surprisingly the genetic deletion of PPARα also abrogated the effect of GW501516 in terms of both weight loss and hepatic lipid accumulation. Also the levels of the PPARα endogenous agonist 16:0/18:1-GPC were shown to be modulated by PPARδ in wild type mice. Our results show that both PPARδ and PPARα receptors are essential for GW501516-driven adipose tissue reduction and subsequently hepatic steatosis, with PPARα working downstream of PPARδ. Wojciech G. Garbacz, Jeffrey T. J. Huang, Larry G. Higgins, Walter Wahli, and Colin N. A. Palmer Copyright © 2015 Wojciech G. Garbacz et al. All rights reserved. Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions Mon, 26 Oct 2015 12:15:30 +0000 http://www.hindawi.com/journals/ppar/2015/271983/ Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs. Wang-Soo Lee and Jaetaek Kim Copyright © 2015 Wang-Soo Lee and Jaetaek Kim. All rights reserved. Therapeutic Actions of the Thiazolidinediones in Alzheimer’s Disease Mon, 26 Oct 2015 08:38:56 +0000 http://www.hindawi.com/journals/ppar/2015/957248/ Alzheimer’s disease (AD) is a multifactorial metabolic brain disorder characterized by protein aggregates, synaptic failure, and cognitive impairment. In the AD brain is common to observe the accumulation of senile plaques formed by amyloid-beta (Aβ) peptide and the neurofibrillary tangles composed of modified tau protein, which both lead to cellular damage and progressive neurodegeneration. Currently, there is no effective therapy for AD; however several studies have shown that the treatments with the peroxisome proliferators activated receptor-gamma (PPARγ) agonists known as thiazolidinedione drugs (TZDs), like rosiglitazone and pioglitazone, attenuate neurodegeneration and improve cognition in mouse models and patients with mild-to-moderate AD. Furthermore, studies on animal models have shown that TZDs inhibit neuroinflammation, facilitate amyloid-β plaque clearance, enhance mitochondrial function, improve synaptic plasticity, and, more recently, attenuate tau hyperphosphorylation. How TZDs may improve or reduce these pathologic signs of AD and what the mechanisms and the implicated pathways in which these drugs work are are questions that remain to be answered. However, in this review, we will discuss several cellular targets, in which TZDs can be acting against the neurodegeneration. María José Pérez and Rodrigo A. Quintanilla Copyright © 2015 María José Pérez and Rodrigo A. Quintanilla. All rights reserved. 15-Deoxy-Δ12,14-Prostaglandin J2 Inhibits Homing of Bone Marrow-Derived Mesenchymal Stem Cells Triggered by Chronic Liver Injury via Redox Pathway Sun, 20 Sep 2015 12:28:27 +0000 http://www.hindawi.com/journals/ppar/2015/876160/ It has been reported that bone marrow-derived mesenchymal stem cells (BMSCs) have capacity to migrate to the damaged liver and contribute to fibrogenesis in chronic liver diseases. 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), an endogenous ligand for peroxisome proliferator-activated receptor gamma (PPARγ), is considered a new inhibitor of cell migration. However, the actions of 15d-PGJ2 on BMSC migration remain unknown. In this study, we investigated the effects of 15d-PGJ2 on the migration of BMSCs using a mouse model of chronic liver fibrosis and primary mouse BMSCs. Our results demonstrated that in vivo, 15d-PGJ2 administration inhibited the homing of BMSCs to injured liver by flow cytometric analysis and, in vitro, 15d-PGJ2 suppressed primary BMSC migration in a dose-dependent manner determined by Boyden chamber assay. Furthermore, the repressive effect of 15d-PGJ2 was blocked by reactive oxygen species (ROS) inhibitor, but not PPARγ antagonist, and action of 15d-PGJ2 was not reproduced by PPARγ synthetic ligands. In addition, 15d-PGJ2 triggered a significant ROS production and cytoskeletal remodeling in BMSCs. In conclusion, our results suggest that 15d-PGJ2 plays a crucial role in homing of BMSCs to the injured liver dependent on ROS production, independently of PPARγ, which may represent a new strategy in the treatment of liver fibrosis. Xin Liu, Shuangshuang Jia, Weiyang Li, Le Yang, Lin Yang, Lin Wang, and Liying Li Copyright © 2015 Xin Liu et al. All rights reserved. Identification of Bexarotene as a PPAR Antagonist with HDX Tue, 15 Sep 2015 14:04:48 +0000 http://www.hindawi.com/journals/ppar/2015/254560/ The retinoid x receptors (RXRs) are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL). The RXRs form heterodimers with several nuclear receptors (NRs), including peroxisome proliferator-activated receptor gamma (PPARγ), to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX) mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions. David P. Marciano, Dana S. Kuruvilla, Bruce D. Pascal, and Patrick R. Griffin Copyright © 2015 David P. Marciano et al. All rights reserved. Review of the Structural and Dynamic Mechanisms of PPARγ Partial Agonism Tue, 08 Sep 2015 09:33:46 +0000 http://www.hindawi.com/journals/ppar/2015/816856/ PPARγ (peroxisome proliferator activated receptor γ) is a ligand activated transcription factor of the nuclear receptor superfamily that controls the expression of a variety of genes involved in fatty acid metabolism, adipogenesis, and insulin sensitivity. While endogenous ligands of PPARγ include fatty acids and eicosanoids, synthetic full agonists of the receptor, including members of the thiazolidinedione (TZD) class, have been widely prescribed for the treatment of type II diabetes mellitus (T2DM). Unfortunately, the use of full agonists has been hampered by harsh side effects with some removed from the market in many countries. In contrast, partial agonists of PPARγ have been shown to retain favourable insulin sensitizing effects while exhibiting little to no side effects and thus represent a new potential class of therapeutics for the treatment of T2DM. Partial agonists have been found to not only display differences in transcriptional and cellular outcomes, but also act through distinct structural and dynamic mechanisms within the ligand binding cavity compared to full agonists. Alice J. Kroker and John B. Bruning Copyright © 2015 Alice J. Kroker and John B. Bruning. All rights reserved. Pharmacogenomics of Drug Response in Type 2 Diabetes: Toward the Definition of Tailored Therapies? Mon, 15 Jun 2015 07:17:10 +0000 http://www.hindawi.com/journals/ppar/2015/415149/ Type 2 diabetes is one of the major causes of mortality with rapidly increasing prevalence. Pharmacological treatment is the first recommended approach after failure in lifestyle changes. However, a significant number of patients shows—or develops along time and disease progression—drug resistance. In addition, not all type 2 diabetic patients have the same responsiveness to drug treatment. Despite the presence of nongenetic factors (hepatic, renal, and intestinal), most of such variability is due to genetic causes. Pharmacogenomics studies have described association between single nucleotide variations and drug resistance, even though there are still conflicting results. To date, the most reliable approach to investigate allelic variants is Next-Generation Sequencing that allows the simultaneous analysis, on a genome-wide scale, of nucleotide variants and gene expression. Here, we review the relationship between drug responsiveness and polymorphisms in genes involved in drug metabolism (CYP2C9) and insulin signaling (ABCC8, KCNJ11, and PPARG). We also highlight the advancements in sequencing technologies that to date enable researchers to perform comprehensive pharmacogenomics studies. The identification of allelic variants associated with drug resistance will constitute a solid basis to establish tailored therapeutic approaches in the treatment of type 2 diabetes. Carla Pollastro, Carmela Ziviello, Valerio Costa, and Alfredo Ciccodicola Copyright © 2015 Carla Pollastro et al. All rights reserved.