PPAR Research http://www.hindawi.com The latest articles from Hindawi Publishing Corporation © 2016 , Hindawi Publishing Corporation . 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. PPAR-Alpha Agonist Used at the Acute Phase of Experimental Ischemic Stroke Reduces Occurrence of Thrombolysis-Induced Hemorrhage in Rats Thu, 28 May 2015 06:03:38 +0000 http://www.hindawi.com/journals/ppar/2015/246329/ The impact of fenofibrate, a peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist, on the risk of thrombolysis-induced hemorrhage during the acute phase of stroke in a rat model of stroke was studied. One-hour middle cerebral artery occlusion followed by thrombolysis with tissue plasminogen activator was made in rats receiving either fenofibrate or vehicle for 72 h after stroke. Evaluation of infarct, hemorrhage, middle cerebral artery vasoreactivity, and immunochemistry (CD11b for microglial activation, myeloperoxidase, and ICAM-1 for neutrophil infiltration) was performed. The PPAR-alpha agonist significantly reduced the risk of hemorrhage after thrombolysis in parallel with a decrease in the infarct volume and in the stroke-induced vascular endothelial dysfunction. These effects are concomitant with a reduction in microglial activation and neutrophil infiltration in infarct area. Our results strengthen the idea that using drugs such as fenofibrate, with pleiotropic properties due to PPAR-alpha agonism, may be of value to reduce thrombolysis-induced hemorrhage during acute stroke. Sophie Gautier, Thavarak Ouk, Maud Pétrault, Olivier Pétrault, Vincent Bérézowski, and Régis Bordet Copyright © 2015 Sophie Gautier et al. All rights reserved. Thiazolidinediones and Edema: Recent Advances in the Pathogenesis of Thiazolidinediones-Induced Renal Sodium Retention Thu, 14 May 2015 13:32:37 +0000 http://www.hindawi.com/journals/ppar/2015/646423/ Thiazolidinediones (TZDs) are one of the major classes of antidiabetic drugs that are used widely. TZDs improve insulin resistance by activating peroxisome proliferator-activated receptor gamma (PPARγ) and ameliorate diabetic and other nephropathies, at least, in experimental animals. However, TZDs have side effects, such as edema, congestive heart failure, and bone fracture, and may increase bladder cancer risk. Edema and heart failure, which both probably originate from renal sodium retention, are of great importance because these side effects make it difficult to continue the use of TZDs. However, the pathogenesis of edema remains a matter of controversy. Initially, upregulation of the epithelial sodium channel (ENaC) in the collecting ducts by TZDs was thought to be the primary cause of edema. However, the results of other studies do not support this view. Recent data suggest the involvement of transporters in the proximal tubule, such as sodium-bicarbonate cotransporter and sodium-proton exchanger. Other studies have suggested that sodium-potassium-chloride cotransporter 2 in the thick ascending limb of Henle and aquaporins are also possible targets for TZDs. This paper will discuss the recent advances in the pathogenesis of TZD-induced sodium reabsorption in the renal tubules and edema. Shoko Horita, Motonobu Nakamura, Nobuhiko Satoh, Masashi Suzuki, and George Seki Copyright © 2015 Shoko Horita et al. All rights reserved. The Role of PPAR Gamma in Systemic Sclerosis Wed, 06 May 2015 16:15:49 +0000 http://www.hindawi.com/journals/ppar/2015/124624/ Fibrosis is recognized as an important feature of many chronic diseases, such as systemic sclerosis (SSc), an autoimmune disease of unknown etiology, characterized by immune dysregulation and vascular injury, followed by progressive fibrosis affecting the skin and multiple internal organs. SSc has a poor prognosis because no therapy has been shown to reverse or arrest the progression of fibrosis, representing a major unmet medical need. Recently, antifibrotic effects of PPARγ ligands have been studied in vitro and in vivo and some theories have emerged leading to new insights. Aberrant PPARγ function seems to be implicated in pathological fibrosis in the skin and lungs. This antifibrotic effect is mainly related to the inhibition of TGF-β/Smad signal transduction but other pathways can be involved. This review focused on recent studies that identified PPARγ as an important novel pathway with critical roles in regulating connective tissue homeostasis, with emphasis on skin and lung fibrosis and its role on systemic sclerosis. Andréa Tavares Dantas, Michelly Cristiny Pereira, Moacyr Jesus Barreto de Melo Rego, Laurindo Ferreira da Rocha Jr., Ivan da Rocha Pitta, Cláudia Diniz Lopes Marques, Angela Luzia Branco Pinto Duarte, and Maira Galdino da Rocha Pitta Copyright © 2015 Andréa Tavares Dantas et al. All rights reserved. Nitrooleic Acid Attenuates Lipid Metabolic Disorders and Liver Steatosis in DOCA-Salt Hypertensive Mice Wed, 11 Mar 2015 07:21:21 +0000 http://www.hindawi.com/journals/ppar/2015/480348/ Nitrooleic acid (OA-NO2) is endogenous ligands for peroxisome proliferator-activated receptors. The present study was aimed at investigating the beneficial effects of OA-NO2 on the lipid metabolism and liver steatosis in deoxycorticosterone acetate- (DOCA-) salt induced hypertensive mice model. Male C57BL/6 mice were divided to receive DOCA-salt plus OA-NO2 or DOCA-salt plus vehicle and another group received neither DOCA-salt nor OA-NO2 (control group). After 3-week treatment with DOCA-salt plus 1% sodium chloride in drinking fluid, the hypertension was noted; however, OA-NO2 had no effect on the hypertension. In DOCA-salt treated mice, the plasma triglyceride and total cholesterol levels were significantly increased compared to control mice, and pretreatment with OA-NO2 significantly reduced these parameters. Further, the histopathology of liver exhibited more lipid distribution together with more serious micro- and macrovesicular steatosis after DOCA-salt treatment and that was consistent with liver tissue triglyceride and nonesterified fatty acids (NEFA) content. The mice pretreated with OA-NO2 showed reduced liver damage accompanied with low liver lipid content. Moreover, the liver TBARS, together with the expressions of gp91phox and p47phox, were parallelly decreased. These findings indicated that OA-NO2 had the protective effect on liver injury against DOCA-salt administration and the beneficial effect could be attributed to its antihyperlipidemic activities. Haiping Wang, Jing Sun, Zhanjun Jia, Tianxin Yang, Liang Xu, Bing Zhao, Kezhou Yu, and Rong Wang Copyright © 2015 Haiping Wang et al. All rights reserved. Huaier Cream Protects against Adriamycin-Induced Nephropathy by Restoring Mitochondrial Function via PGC-1 Upregulation Wed, 11 Mar 2015 07:11:13 +0000 http://www.hindawi.com/journals/ppar/2015/720383/ The mechanism by which Huaier, a Chinese traditional medicine, protects podocytes remains unclear. We designed the present study to examine whether mitochondrial function restored by PGC-1 serves as the major target of Huaier cream in protecting ADR nephropathy. After ADR administration, the podocytes exhibited remarkable cell injury and mitochondrial dysfunction. Additionally, ADR also reduced PGC-1 both in vivo and in vitro. Following the Huaier treatment, the notable downregulation of PGC-1 and its downstream molecule mitochondrial transcription factor A (TFAM) were almost entirely blocked. Correspondingly, Huaier markedly ameliorated ADR-induced podocyte injury and mitochondrial dysfunction in both rat kidneys and incubated cells as it inhibited the decrease of nephrin and podocin expression, mtDNA copy number, MMP, and ATP content. Transmission electron microscopy result also showed that Huaier protected mitochondria against ADR-induced severe mitophagy and abnormal changes of ultrastructural morphology. In conclusion, Huaier can protect podocytes against ADR-induced cytotoxicity possibly by reversing the dysfunction of mitochondria via PGC-1 overexpression, which may be a novel therapeutic drug target in glomerular diseases. Ruochen Che, Chunhua Zhu, Guixia Ding, Min Zhao, Mi Bai, Zhanjun Jia, Aihua Zhang, and Songming Huang Copyright © 2015 Ruochen Che et al. 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.