http://www.hindawi.comThe latest articles from Hindawi Publishing Corporation© 2012, Hindawi Publishing Corporation. All rights reserved.http://www.hindawi.com/journals/ppar/2012/616371/The paraoxonase (PON) group of enzymes, composed of PON1, PON2, and PON3, play an important role in decreasing oxidative stress by degrading lipid peroxides. PON1 synthesis is upregulated by PPAR. Several pharmacological compounds (acting as antioxidants and, hence, atheroprotective) stimulate both PPAR activity and PON1 expression. Recent evidence suggests that PON1 and the monocyte chemoattractant protein-1 (MCP-1) are involved in coordinating the inflammatory response in damaged tissues; PPAR may be central in the regulation of these biochemical pathways. This article reviews the state of knowledge on PON1 biochemistry and function, the influence of genetic variation, and the regulation of PON1 expression by pharmaceutical compounds that increase PPAR activity. We also describe recent lines of evidence suggesting links between PON1 and MCP-1 and how their production may be regulated by PPAR.Jordi Camps, Anabel García-Heredia, Anna Rull, Carlos Alonso-Villaverde, Gerard Aragonès, Raúl Beltrán-Debón, Esther Rodríguez-Gallego, and Jorge JovenCopyright © 2012 Jordi Camps et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/171765/Undifferentiated (anaplastic) thyroid cancer (ATC) is one of the most aggressive human malignancies and no effective therapy is currently available. We show here that PPARγ levels are elevated in cells derived from ATC. Depletion of PPARγ in HTh74 ATC cells resulted in decreased cell growth, cell cycle arrest and a reduction in pRb and cyclin A and B1 levels. We further showed that both flank and orthotopic thyroid tumors derived from PPARγ-depleted cells grew more slowly than PPARγ-expressing cells. When PPARγ was overexpressed in more differentiated thyroid cancer BCPAP cells which lack PPARγ, there was increased growth and raised pRb and cyclin A and B1 levels. Finally, PPARγ depletion in ATC cells decreased their invasive capacity whereas overexpression in PTC cells increased invasiveness. These data suggest that PPARγ may play a detrimental role in thyroid cancer and that targeting it therapeutically may lead to improved treatment of advanced thyroid cancer.William M. Wood, Vibha Sharma, Kevin T. Bauerle, Laura A. Pike, Qiong Zhou, Deborah L. Fretwell, Rebecca E. Schweppe, and Bryan R. HaugenCopyright © 2011 William M. Wood et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/840194/Peroxisome proliferator-activated receptor γ (PPARγ) forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs). It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.Atsuki Yamamoto, Hiroki Kakuta, Hiroyuki Miyachi, and Yukio SugimotoCopyright © 2011 Atsuki Yamamoto et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/502631/Peroxisome proliferator-activated receptor-alpha (PPAR-α) activation by fenofibrate reduces blood pressure and sodium retention during DOCA-salt hypertension. PPAR-α activation reduces the expression of inflammatory cytokines, such as interleukin-6 (IL-6). Fenofibrate also induces cytochrome P450 4A (CYP4A) and increases 20-hydroxyeicosatetraenoic acid (20-HETE) production. This study tested whether the administration of fenofibrate would reduce blood pressure by attenuating plasma IL-6 and renal expression of cyclooxygenase-2 (COX-2), while increasing expression of renal CYP4A during 7 days of DOCA-salt hypertension. We performed uni-nephrectomy on 12–14 week old male Swiss Webster mice and implanted biotelemetry devices in control, DOCA-salt (1.5 mg/g) treated mice with or without fenofibrate (500 mg/kg/day in corn oil, intragastrically). Fenofibrate significantly decreased mean arterial pressure and plasma IL-6. In kidney homogenates, fenofibrate increased CYP4A and decreased COX-2 expression. There were no differences in renal cytochrome P450, family 2, subfamily c, polypeptide 23 (CYP2C23) and soluble expoxide hydrolase (sEH) expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR-α activation by fenofibrate involves the reduction of plasma IL-6 and COX-2, while increasing CYP4A expression during DOCA-salt hypertension. Our results may also suggest that PPAR-α activation protects the kidney against renal injury via decreased COX-2 expression.Dexter L. Lee, Justin L. Wilson, Rong Duan, Tamaro Hudson, and Ahmed El-MarakbyCopyright © 2011 Dexter L. Lee et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/436358/This study explores the skeletal effects of the peroxisome proliferator activated receptor (PPAR)pan agonist tetradecylthioacetic acid (TTA). Rats, without (Study I) and with ovariectomy (OVX) or sham operation (Study II), were given TTA or vehicle daily for 4 months. Bone markers in plasma, whole body and femoral bone mineral density and content (BMD and BMC), and body composition were examined. Histomorphometric and biomechanical analyses (Study I) and biomechanical and μCT analyses (Study II) of the femur were performed. Normal rats fed TTA had higher femoral BMD and increased total and cortical area in femur compared to controls. The ovariectomized groups had decreased BMD and impaired microarchitecture parameters compared to SHAM. However, the TTA OVX group maintained femoral BMC, trabecular thickness in the femoral head, and cortical volume in the femoral metaphysis as SHAM. TTA might increase BMD and exert a light preventive effect on estrogen-related bone loss in rats.Astrid Kamilla Stunes, Irene Westbroek, Reidar Fossmark, Rolf Kristian Berge, Janne Elin Reseland, and Unni SyversenCopyright © 2011 Astrid Kamilla Stunes et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/523520/Tetrahydrobiopterin (BH4) is an essential cofactor for endothelial nitric oxide (NO) synthase. Guanosine 5′-triphosphate cyclohydrolase-I (GTPCH-I) is a key limiting enzyme for BH4 synthesis. In the present in vitro study, we investigated whether peroxisome proliferator-activated receptor α (PPAR-α) agonist fenofibrate could recouple eNOS by reversing low-expression of intracellular BH4 in endothelial cells and discussed the potential mechanisms. After human umbilical vein endothelial cells (HUVECs) were treated with lipopolysaccharide (LPS) for 24 hours, the levels of cellular eNOS, BH4 and cell supernatant NO were significantly reduced compared to control group. And the fluorescence intensity of intracellular ROS was significantly increased. But pretreated with fenofibrate (10 umol/L) for 2 hours before cells were induced by LPS, the levels of eNOS, NO, and BH4 were significantly raised compared to LPS treatment alone. ROS production was markedly reduced in fenofibrate group than LPS group. In addition, our results showed that the level of intracellular GTPCH-I detected by western blot was increased in a concentration-dependent manner after being treated with fenofibrate. These results suggested that fenofibrate might help protect endothelial function and against atherosclerosis by increasing level of BH4 and decreasing production of ROS through upregulating the level of intracellular GTPCH-I.Jinbo Liu, Changlin Lu, Fuwang Li, Haining Wang, Liyun He, Yanting Hao, Alex F. Chen, Huijie An, Xian Wang, Tianpei Hong, and Guang WangCopyright © 2011 Jinbo Liu et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/164925/Hepatic nuclear factor 4α (HNF4α) modulates the transcriptional activation of numerous metabolic genes in liver. In this study, gene-array analysis revealed that HNF4α overexpression increased peroxisome proliferator-activated receptorγ (PPARγ) greatly in cultured rat primary hepatocytes. PPAR-response-element-driven reporter gene expression could be elevated by HNF4α. Bioinformatics analysis revealed a high-affinity HNF4α binding site in the human PPARγ2 promoter and in vitro experiments showed that this promoter could be transactivated by HNF4α. The presence of HNF4α on the promoter was then confirmed by ChIP assay. In vivo, hepatic overexpression of HNF4α decreased cholesterol levels both in plasma and liver and several hepatic genes related to cholesterol metabolism, including scavenger receptor BI (SR-BI), were upregulated. The upregulation of SR-BI by HNF4α could be inhibited by a PPARγ antagonist in vitro. In conclusion, HNF4α regulates cholesterol metabolism in rat by modulating the expression of SR-BI in the liver, in which the upregulation of PPARγ was involved.Yi Zhang, Chen Shen, Ding Ai, Xuefen Xie, and Yi ZhuCopyright © 2011 Yi Zhang et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/373560/Peroxisome proliferator-activated receptors (PPARα, δ, and γ) are ligand-activated transcription factors that regulate a wide range of cellular processes, including inflammation, proliferation, differentiation, metabolism, and energy homeostasis. All three PPAR subtypes have been identified in the central nervous system (CNS) of rodents. While PPARα and PPARγ are expressed in more restricted areas of the CNS, PPARδ is ubiquitously expressed and is the predominant subtype. Although data regarding PPARδ are limited, studies have demonstrated that administration of PPARδ agonists confers neuroprotection following various acute and chronic injuries to the CNS, such as stroke, multiple sclerosis, and Alzheimer's disease. The antioxidant and anti-inflammatory properties of PPARδ agonists are thought to underly their neuroprotective efficacy. This review will focus on the putative neuroprotective benefits of therapeutically targeting PPARδ in the CNS, and specifically, highlight the antioxidant and anti-inflammatory functions of PPARδ agonists.Caroline I. Schnegg and Mike E. RobbinsCopyright © 2011 Caroline I. Schnegg and Mike E. Robbins. All rights reserved.http://www.hindawi.com/journals/ppar/2011/753917/Atherogenic ω-6 lipids are physiological ligands of peroxisome proliferator-activated receptors (PPARs) and elicit pro- and antiatherogenic responses in vascular cells. The objective of this study was to investigate if ω-6 lipids modulated the early growth response-1 (Egr-1)/PPAR crosstalk thereby altering vascular function. Rat aortic smooth muscle cells (RASMCs) were exposed to ω-6 lipids, linoleic acid (LA), or its oxidized form, 13-HPODE (OxLA) in the presence or absence of a PPARα antagonist (MK886) or PPARγ antagonist (GW9662) or PPAR-specific siRNA. Our results demonstrate that ω-6 lipids, induced Egr-1 and monocyte chemotactic protein-1 (MCP-1) mRNA and protein levels at the acute phase (1–4 hrs) when PPARα was downregulated and at subacute phase (4–12 hrs) by modulating PPARγ, thus resulting in altered monocyte adhesion to RASMCs. We provide novel insights into the mechanism of action of ω-6 lipids on Egr-1/PPAR interactions in vascular cells and their potential in altering vascular function.Jia Fei, Carla Cook, Miriah Gillespie, Bangning Yu, Khyra Fullen, and Nalini SantanamCopyright © 2011 Jia Fei et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/179454/Growing evidence indicates that PPARγ agonists, including rosiglitazone (RSG), induce adipose mitochondrial biogenesis. By systematically analyzing mitochondrial gene expression in two common murine adipocyte models, the current study aimed to further establish the direct role of RSG and capture temporal changes in gene transcription. Microarray profiling revealed that in fully differentiated 3T3-L1 and C3H/10T1/2 adipocytes treated with RSG or DMSO vehicle for 1, 2, 4, 7, 24, and 48 hrs, RSG overwhelmingly increased mitochondrial gene transcripts time dependently. The timing of the increases was consistent with the cascade of organelle biogenesis, that is, initiated by induction of transcription factor(s), followed by increases in the biosynthesis machinery, and then by increases in functional components. The transcriptional increases were further validated by increased mitochondrial staining, citrate synthase activity, and O2 consumption, and were found to be associated with increased adiponectin secretion. The work provided further insight on the mechanism of PPARγ-induced mitochondrial biogenesis in differentiated adipocytes.James X. Rong, Jean-Louis D. Klein, Yang Qiu, Mi Xie, Jennifer H. Johnson, K. Michelle Waters, Vivian Zhang, Jennifer A. Kashatus, Katja S. Remlinger, Nan Bing, Renae M. Crosby, Tymissha K. Jackson, Sam M. Witherspoon, John T. Moore, Terence E. Ryan, Sue D. Neill, and Jay C. StrumCopyright © 2011 James X. Rong et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/742785/Members of the nuclear receptor superfamily have vital roles in regulating immunity and inflammation. The founding member, glucocorticoid receptor (GR), is the prototype to demonstrate immunomodulation via transrepression of the AP-1 and NF-κB signaling pathways. Peroxisome proliferator-activated receptors (PPARs) have emerged as key regulators of inflammation. This review examines the history and current advances in nuclear receptor regulation of inflammation by the crosstalk with AP-1 and NF-κB signaling, focusing on the roles of GR and PPARs. A better understanding of the molecular mechanism by which nuclear receptors inhibit proinflammatory signaling pathways will enable novel therapies to treat chronic inflammation.Min-Dian Li and Xiaoyong YangCopyright © 2011 Min-Dian Li and Xiaoyong Yang. All rights reserved.http://www.hindawi.com/journals/ppar/2011/256186/Glutathione (GSH) derives from cysteine and plays a key role in redox status. GSH synthesis is determined mainly by cysteine availability and γ-glutamate cysteine ligase (γGCL) activity. Because PPARα activation is known to control the metabolism of certain amino acids, GSH synthesis from cysteine and related metabolisms were explored in wild-type (WT) and PPARα-null (KO) mice, fed diets containing either saturated (COCO diet) or 18 : 3 n-3, LIN diet. In mice fed the COCO diet, but not in those fed the LIN diet, PPARα deficiency enhanced hepatic GSH content and γGCL activity, superoxide dismutase 2 mRNA levels, and plasma uric acid concentration, suggesting an oxidative stress. In addition, in WT mice, the LIN diet increased the hepatic GSH pool, without effect on γGCL activity, or change in target gene expression, which rules out a direct effect of PPARα. This suggests that dietary 18 : 3 n-3 may regulate GSH metabolism and thus mitigate the deleterious effects of PPARα deficiency on redox status, without direct PPARα activation.Najoua Guelzim, Jean-François Huneau, Véronique Mathé, Annie Quignard-Boulangé, Pascal G. Martin, Daniel Tomé, and Dominique HermierCopyright © 2011 Najoua Guelzim et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/372854/It is well documented that PPARα and PPARβ/δ share overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPARβ/δ deficiency in mice leads to severe cardiac pathological development, whereas global PPARα knockout shows a benign cardiac phenotype. It is unknown whether a PPARα-null background would alter the pathological development in mice with cardiomyocyte-restricted PPARβ/δ deficiency. In the present study, a mouse model with long-term PPARβ/δ deficiency in PPARα-null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPARα-null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPARβ/δ deficiency. Moreover, PPARα-null did not alter the phenotypic development in adult mice with the short-term deletion of PPARβ/δ in their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPARβ/δ in PPARα-null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPARβ/δ is essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPARα.Jian Liu, Peiyong Wang, Lan He, Yuquan Li, Jinwen Luo, Lihong Cheng, Qianhong Qin, Lawrence A. Brako, Woo-kuen Lo, William Lewis, and Qinglin YangCopyright © 2011 Jian Liu et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/629728/Gene expression profiling of PPARα has been used in several studies, but fewer studies went further to identify the tissue-specific pathways or genes involved in PPARα activation in genome-wide. Here, we employed and applied gene set enrichment analysis to two microarray datasets both PPARα related respectively in mouse liver and intestine. We suggested that the regulatory mechanism of PPARα activation by WY14643 in mouse small intestine is more complicated than in liver due to more involved pathways. Several pathways were cancer-related such as pancreatic cancer and small cell lung cancer, which indicated that PPARα may have an important role in prevention of cancer development. 12 PPARα dependent pathways and 4 PPARα independent pathways were identified highly common in both liver and intestine of mice. Most of them were metabolism related, such as fatty acid metabolism, tryptophan metabolism, pyruvate metabolism with regard to PPARα regulation but gluconeogenesis and propanoate metabolism independent of PPARα regulation. Keratan sulfate biosynthesis, the pathway of regulation of actin cytoskeleton, the pathways associated with prostate cancer and small cell lung cancer were not identified as hepatic PPARα independent but as WY14643 dependent ones in intestinal study. We also provided some novel hepatic tissue-specific marker genes.Kan He, Qishan Wang, Yumei Yang, Minghui Wang, and Yuchun PanCopyright © 2011 Kan He et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/647017/Background. This study was performed to investigate the influence of a short-term treatment with pioglitazone versus placebo on inflammatory activation of mononuclear cells (mRNA expression/protein secretion of inflammatory markers). Methods and Results. Sixty-three patients with well-controlled type 2 diabetes (52 males, 11 females, age (Mean ± SD): 66±7 yrs, disease duration: 6.6±9.6 yrs, HbA1c: 6.7±0.6%) were randomized to additional 45 mg of pioglitazone or placebo to their existing metformin and sulfonylurea therpay for four weeks in a double-blind study design. Protein risk marker levels (hsCRP, MMP-9, MCP-1, etc.) and the expression of NFκB subunits and NFκB-modulated cytokines from isolated peripheral monocyte/macrophages were determined at baseline and endpoint. There were no changes in HbA1c, but significant biomarker improvements were seen with pioglitazone only. The mRNA marker expression was downregulated by pioglitazone and further up-regulated with placebo (e.g., P105 pioglitazone: −19%/placebo: +6%, RelA: −20%/+2%, MMP−9: −36%/+9%, TNFα: −10%/+14%, P<0.05 between groups in all cases). Conclusions. Pioglitazone very rapidly down-regulated the activated state of peripheral monocytes/macrophages as assessed by mRNA expression of NFκB and NFκB-modulated cytokines and decreased plasma levels of cardiovascular risk marker proteins independent of glycemic control.Andreas Pfützner, Alexander Weise, Elisabeth Pfützner-Riehn, Georg Lübben, Michael Morcos, Efstrathios Karagiannis, Matthias Weber, and Thomas ForstCopyright © 2011 Andreas Pfützner et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/318134/Acute and chronic lung inflammation is associated with numerous important disease pathologies including asthma, chronic obstructive pulmonary disease and silicosis. Lung fibroblasts are a novel and important target of anti-inflammatory therapy, as they orchestrate, respond to, and amplify inflammatory cascades and are the key cell in the pathogenesis of lung fibrosis. Peroxisome proliferator-activated receptor gamma (PPARγ) ligands are small molecules that induce anti-inflammatory responses in a variety of tissues. Here, we report for the first time that PPARγ ligands have potent anti-inflammatory effects on human lung fibroblasts. 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO) and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibit production of the inflammatory mediators interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), COX-2, and prostaglandin (PG)E2 in primary human lung fibroblasts stimulated with either IL-1β or silica. The anti-inflammatory properties of these molecules are not blocked by the PPARγ antagonist GW9662 and thus are largely PPARγ independent. However, they are dependent on the presence of an electrophilic carbon. CDDO and 15d-PGJ2, but not rosiglitazone, inhibited NF-κB activity. These results demonstrate that CDDO and 15d-PGJ2 are potent attenuators of proinflammatory responses in lung fibroblasts and suggest that these molecules should be explored as the basis for novel, targeted anti-inflammatory therapies in the lung and other organs.Christopher M. Hogan, Thomas H. Thatcher, Ramil E. Sapinoro, Michael N. Gurell, Heather E. Ferguson, Stephen J. Pollock, Carolyn Jones, Richard P. Phipps, and Patricia J. SimeCopyright © 2011 Christopher M. Hogan et al. All rights reserved.http://www.hindawi.com/journals/ppar/2011/261584/Restricted feeding (RF) during daytime is associated with anticipatory activity before feeding, marked hyperphagia after mealtime, adjustments in hepatic metabolism, and the expression of a food-entrained oscillator (FEO). 24 h rhythmicity of liver PPARα, β, and γ, peroxisomal markers (PMP70, AOX, and catalase), and free fatty acids (FFAs) during RF was evaluated. The effect of fasting-refeeding was also studied. Results showed (1) higher levels of FFA before feeding, (2) a shift of PPARα and PPARγ before and of PPARβ peaks after feeding, (3) an increase in peroxisomal markers, (4) a shift of PMP70 and AOX peaks before feeding, and of maximal catalase activity in the dark period, (5) changes in the fasting-refeeding response, and (6) high correlations (>0.9) of serum corticosterone with PPARα and PPARγ and of PMP70 with PPARβ. In conclusion, 24 h rhythmicity of FFA, liver PPARs, and peroxisomal markers are biochemical adaptations associated with daytime RF and FEO expression.Julieta B. Rivera-Zavala, Adrián Báez-Ruiz, and Mauricio Díaz-MuñozCopyright © 2011 Julieta B. Rivera-Zavala et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/352957/PPARα and HNF4α are nuclear receptors that control gene transcription by direct binding to specific nucleotide sequences. Using transgenic mice deficient for either PPARα or HNF4α, we show that the expression of the peroxisomal 3-keto-acyl-CoA thiolase B (Thb) is under the dependence of these two transcription factors. Transactivation and gel shift experiments identified a novel PPAR response element within intron 3 of the Thb gene, by which PPARα but not HNF4α transactivates. Intriguingly, we found that HNF4α enhanced PPARα/RXRα transactivation from TB PPRE3 in a DNA-binding independent manner. Coimmunoprecipitation assays supported the hypothesis that HNF4α was physically interacting with RXRα. RT-PCR performed with RNA from liver-specific HNF4α-null mice confirmed the involvement of HNF4α in the PPARα-regulated induction of Thb by Wy14,643. Overall, we conclude that HNF4α enhances the PPARα-mediated activation of Thb gene expression in part through interaction with the obligate PPARα partner, RXRα.J. Chamouton, F. Hansmannel, J. A. Bonzo, M. C. Clémencet, G. Chevillard, M. Battle, P. Martin, T. Pineau, S. Duncan, F. J. Gonzalez, N. Latruffe, S. Mandard, and V. Nicolas-FrancèsCopyright © 2010 J. Chamouton et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/153252/Isoflavone intake through foods and dietary supplements has both health advocates and critics. The latter come from a concern about the estrogenic effects of isoflavones in certain species. However, careful removal of isoflavones and other estrogens from the diet of rodents leads to the metabolic syndrome. These results suggest that isoflavones have other mechanisms of action, potentially those involving regulation of fatty acid metabolism via the nuclear receptors PPARα and PPARγ. The goal of this paper was to examine the evidence for isoflavone/PPAR signaling and to identify diseases in which such signaling would have an important impact. It is therefore of note that investigators using a chemical structure approach to discover PPAR ligands identified isoflavones as the best structures in the library of compounds that they tested. Future studies will involve careful identification of the underlying mechanisms whereby isoflavones have their action via PPAR signaling.Rakesh P. Patel and Stephen BarnesCopyright © 2010 Rakesh P. Patel and Stephen Barnes. All rights reserved.http://www.hindawi.com/journals/ppar/2010/571783/Peroxisome proliferator-activated receptorδ (PPARδ) regulates a multiplicity of physiological processes associated with glucose and lipid metabolism, inflammation, and proliferation. One or more of these processes likely create risk factors associated with the ability of PPARδ agonists to promote tumorigenesis in some organs. In the present study, we describe a new gastric tumor mouse model that is dependent on the potent and highly selective PPARδ agonist GW501516 following carcinogen administration. The progression of gastric tumorigenesis was rapid as determined by magnetic resonance imaging and resulted in highly metastatic squamous cell carcinomas of the forestomach within two months. Tumorigenesis was associated with gene expression signatures indicative of cell adhesion, invasion, inflammation, and metabolism. Increased PPARδ expression in tumors correlated with increased PDK1, Akt, β-catenin, and S100A9 expression. The rapid development of metastatic gastric tumors in this model will be useful for evaluating preventive and therapeutic interventions in this disease.Claire B. Pollock, Olga Rodriguez, Philip L. Martin, Chris Albanese, Xin Li, Levy Kopelovich, and Robert I. GlazerCopyright © 2010 Claire B. Pollock et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/193019/We have investigated the effects of WY14643, a potent peroxisome proliferator activator receptor-α (PPAR-α) agonist, in a rat model of ligature-induced periodontitis. Male Sprague-Dawley rats were lightly anaesthetized with pentobarbitone (35 mg/kg). Sterile, 2-0 black braided silk thread was placed around the cervix of the lower left first molar and knotted medially. Animals received WY14643 (1 mg/kg i.p, daily for eight days). Eighths days after placement of the ligature, we evaluated several markers of inflammation such us (1) myeloperoxidase activity, (2) a cytokines and adhesion molecules expression, (3) NF-κB expression, (4) iNOS expression, (5) the nitration of tyrosine residues, (6) activation of the nuclear enzyme poly(ADP-ribose) polymerase, (7) apoptosis, and (8) the degree of gingivomucosal tissues injury. Administration of WY14643 significantly decreased all of the parameters of inflammation as described above. These results demonstrate that WY14643 exerts an anti-inflammatory role during experimental periodontitis and is able to ameliorate the tissue damage.Enrico Briguglio, Rosanna Di Paola, Irene Paterniti, Emanuela Mazzon, Giacomo Oteri, Giancarlo Cordasco, and Salvatore CuzzocreaCopyright © 2010 Enrico Briguglio et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/104705/PPARs are members of the steroid hormone nuclear receptor superfamily and play an important role in regulating inflammation as well as lipid metabolism. The PPAR subfamily has been defined as PPARα, PPARβ/δ, and PPARγ, each with different ligands, target genes, and biological roles. PPARs regulate the expression of target inflammatory genes through mechanisms involving both transactivation and transrepression. The anti-inflammatory properties of PPAR agonists have led to the investigation of PPAR functions in regulating autoimmune encephalomyelitis. This paper will summarize some of the general mechanisms by which PPARs regulate inflammatory gene expression and focus on the recent advances of PPAR regulation of autoimmune encephalomyelitis.Yuhong Yang, Amy E. Lovett-Racke, and Michael K. RackeCopyright © 2010 Yuhong Yang et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/129173/PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR), and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041) for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.Timothy R. H. Regnault, Lin Zhao, Jacky S. S. Chiu, Stephanie K. Gottheil, Allison Foran, and Siu-Pok YeeCopyright © 2010 Timothy R. H. Regnault et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/345098/Peroxisome proliferator-activated receptor (PPAR)-α, a member of a large nuclear receptor superfamily, plays a major role in the regulation of lipid metabolism. Recently, PPARα activation has been shown to confer additional benefits on endothelial function, kidney function, and anti-inflammation, suggesting that PPARα agonists may be good candidates for treating acute renal failure. In clinical application, PPAR-α activators, such as hypolipidemic drugs in fibric acid class, were proven to have therapeutic effects on metabolic syndrome and cardiovascular disease. This paper focuses on signaling pathways, ligand selectivity, and physio-pathological roles of PPARα in kidney diseases and the therapeutic utility of PPARα modulators in the treatment of diabetes and inflammation-induced nephropathy. Implication of new and more potent PPAR-α activators could provide important insights into the overall benefits of activating PPAR-α clinically for the treatment of dyslipidemia and the prevention of diabetic or inflammation-induced nephropathy in the future.Ching-Feng Cheng, Hsi-Hsien Chen, and Heng LinCopyright © 2010 Ching-Feng Cheng et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/274376/Polycystic kidney disease (PKD) is a genetic disorder characterized by growth of fluid-filled cysts predominately in kidney tubules and liver bile ducts. Currently, the clinical management of PKD is limited to cyst aspiration, surgical resection or organ transplantation. Based on an observation that PPARγ agonists such as pioglitazone and rosiglitazone decrease mRNA levels of a Cl− transport protein, CFTR (cystic fibrosis transmembrane conductance regulator), and the Cl− secretory response to vasopressin in cultured renal cells, it is hypothesized that PPARγ agonists will inhibit cyst growth. The current studies show that a 7- or 14-week pioglitazone feeding regimen inhibits renal and hepatic bile duct cyst growth in the PCK rat, a rodent model orthologous to human PKD. These studies provide proof of concept for the mechanism of action of the PPARγ agonists and suggest that this class of drugs may be effective in controlling both renal and hepatic cyst growth and fibrosis in PKD.Bonnie L. Blazer-Yost, Julie Haydon, Tracy Eggleston-Gulyas, Jey-Hsin Chen, Xiaofang Wang, Vincent Gattone, and Vicente E. TorresCopyright © 2010 Bonnie L. Blazer-Yost et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/635912/Background and Purpose. We investigated the potency of Peroxisome Proliferators-Activated Receptors (PPARs) α, β/δ, and γ agonists to modulate Transforming Growth Factor-β1 (TGF-β1-) induced collagen production or changes in Tissue Inhibitor of Matrix Metalloproteinase- (TIMP-) 1/Matrix Metalloproteinase (MMP) balance in rat chondrocytes embedded in alginate beads. Experimental Approach. Collagen production was evaluated by quantitative Sirius red staining, while TIMP-1 protein levels and global MMP (-1, -2, -3, -7, and -9) or specific MMP-13 activities were measured by ELISA and fluorigenic assays in culture media, respectively. Levels of mRNA for type II collagen, TIMP-1, and MMP-3 & 13 were quantified by real-time PCR. Key Results. TGF-β1 increased collagen deposition and type II collagen mRNA levels, while inducing TIMP-1 mRNA and protein expression. In contrast, it decreased global MMP or specific MMP-13 activities, while decreasing MMP-3 or MMP-13 mRNA levels. PPAR agonists reduced most of the effects of TGF-β1 on changes in collagen metabolism and TIMP-1/MMP balance in rat in a PPAR-dependent manner, excepted for Wy14643 on MMP activities. Conclusions and Implications. PPAR agonists reduce TGF-β1-modulated ECM turnover and inhibit chondrocyte activities crucial for collagen biosynthesis, and display a different inhibitory profile depending on selectivity for PPAR isotypes.Paul-Emile Poleni, Stephanie Etienne, Emilie Velot, Patrick Netter, and Arnaud BianchiCopyright © 2010 Paul-Emile Poleni et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/572405/Tight control of storage and synthesis of glucose during nutritional transitions is essential to maintain blood glucose levels, a process in which the liver has a central role. PPARα is the master regulator of lipid metabolism during fasting, but evidence is emerging for a role of PPARα in balancing glucose homeostasis as well. By using PPARα ligands and PPARα−/− mice, several crucial genes were shown to be regulated by PPARα in a direct or indirect way. We here review recent evidence that PPARα contributes to the adaptation of hepatic carbohydrate metabolism during the fed-to-fasted or fasted-to-fed transition in rodents.Annelies Peeters and Myriam BaesCopyright © 2010 Annelies Peeters and Myriam Baes. All rights reserved.http://www.hindawi.com/journals/ppar/2010/108632/Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is known to play a central role in lipid metabolism and insulin sensitivity as well as inflammation and cell proliferation. According to the results obtained from studies on several animal models of gastrointestinal inflammation, PPARγ has been implicated in the regulation of the immune response, particularly inflammation control, and has gained importance as a potential therapeutic target in the management of gastrointestinal inflammation. In the present paper, we present the current knowledge on the role of PPARγ ligands in the gastrointestinal tract.Yuji Naito, Tomohisa Takagi, and Toshikazu YoshikawaCopyright © 2010 Yuji Naito et al. All rights reserved.http://www.hindawi.com/journals/ppar/2010/417646/Peroxisome proliferator-activated receptors (PPARs) were reported to prevent cells from stress-induced apoptosis and protect tissues against ischemia-reperfusion injury. The underlying transcriptional mechanism is unclear. Recent reports indicate that the antiapoptotic actions of ligand-activated PPARδ and PPARγ are mediated through enhanced binding of PPAR to the promoter of 14-3-3ε and upregulation of 14-3-3ε expression. We propose that ligand-activated PPARα exerts its anti-apoptotic actions via the identical pathway. The PPAR to 14-3-3 transcriptional axis plays an important role in protection of cell and tissue integrity and is a target for drug discovery.Kenneth K. WuCopyright © 2010 Kenneth K. Wu. All rights reserved.http://www.hindawi.com/journals/ppar/2010/937123/PPARγ coactivator-1α (PGC-1α) is considered to be a major regulator of mitochondrial biogenesis. Though first discovered in brown adipose tissue, this coactivator has emerged as a coordinator of mitochondrial biogenesis in skeletal muscle via enhanced transcription of many nuclear genes encoding mitochondrial proteins. Stimuli such as exercise provoke the activation of signalling cascades that lead to the induction of PGC-1α. Posttranslational modifications also regulate the function of PGC-1α, with a multitude of upstream molecules targeting the protein to modify its activity and/or expression. Previous research has established a positive correlation between resistance to fatigue and skeletal muscle mitochondrial content. Recently, studies have begun to elucidate the specific role of PGC-1α in exercise-related skeletal muscle adaptations, with several studies identifying it as a dominant regulator of organelle synthesis. This paper will highlight the function, regulation, and expression of PGC-1α, as well as the role of the coactivator during exercise adaptations.Giulia Uguccioni, Donna D'souza, and David A. HoodCopyright © 2010 Giulia Uguccioni et al. All rights reserved.