BACKGROUNDS/AIMS: During the acute phase response, cytokines induce marked alterations in lipid metabolism including an increase in serum triglyceride levels and a decrease in hepatic fatty acid oxidation, in bile acid synthesis, and in high-density lipoprotein levels. METHODS: Peroxisome proliferator-activated receptors (PPARs: PPARalpha, beta/delta, and gamma) regulate fatty acid metabolism, glucose homeostasis, cell proliferation, differentiation and inflammation. Proinflammatory profiles including tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and interleukin-6 (IL-6) are the important pathological factors in inflammatory responses during the pathological progression of the acute phase response. Lipopolysaccarides (LPS) induced the expression of TNF-alpha, IL-1beta, and IL-6. LPS-induced inflammation decrease the expression of peroxisome proliferator-activated receptor alpha (PPARalpha), PPARbeta/delta, PPARgamma, and coactivators PPARgamma co-activator 1 alpha (PGC-1alpha), PGC-1beta messenger RNA (mRNA) in the liver of Balb/c mouse. In addition, LPS-induced inflammation diminishes the protein level of PPARalpha, PPARbeta/delta, and PPARgamma. Proinflammatory cytokines including TNFalpha, IL-1beta, and IL-6 are the principal reducer of PPARs. However, the knockout mouse model against TNFalpha and IL-6 does not block decrease of PPARs in serum and liver. The mice were pretreated with fenofibrate at 100 mg/kg for 2 days. RESULTS: These treatment protocols increased the amount of PPARs mRNA in the liver. Fenofibrate inhibited LPS-induced TNF-alpha, IL-1beta, and IL-6 production in the serum and liver. Similar results were obtained when human hepatoma HepG2 cells exposed to LPS were co-incubated with fenofibrate. LPS-treated HepG2 cells decreased expression of IkappaB. Moreover, activation of PPARs abrogated LPS-induced degradation of IkappaB, thus suppressing LPS-induced NF-kappaB activities. CONCLUSIONS: Therefore, fenofibrate decreases the expression and secretion of TNF-alpha, IL-1beta, and IL-6 via the NF-kappaB signaling pathway, thus serving as therapeutic targets to attenuate inflammation that is involved in hepatic pathological progression.
Animals ; Bile ; Carcinoma, Hepatocellular ; Cell Proliferation ; Clinical Protocols ; Cytokines ; Fenofibrate ; Glucose ; Hep G2 Cells ; Homeostasis ; Humans ; Inflammation ; Interleukin-1beta ; Interleukin-6 ; Lipid Metabolism ; Lipoproteins ; Liver ; Mice ; Mice, Knockout ; NF-kappa B ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; PPAR alpha ; PPAR-beta ; PPAR delta ; PPAR gamma ; RNA, Messenger ; Tumor Necrosis Factor-alpha

OBJECTIVETo examine the main effect of 10 Peroxisome proliferators-activated receptor (PPAR) SNP in contribution to non-HDL-C and study whether there is an interaction in the 10 SNPs.

METHODSParticipants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort-population-survey, which was initiated from April 1999 to June 2004, and 5-year follow-up data from total 4 582 subjects were obtained between March 2006 and October 2007. A total of 4 083 participants received follow-up examination. After excluding subjects who had experienced stroke or exhibited cardiovascular disease, type 2 diabetes or a BMI <18.5 kg/m(2), a total of 820 unrelated individual subjects were selected from 3 731 subjects on October of 2009. Blood samples which were collected at the baseline were subjected to PPAR&alpha;, PPAR&delta; and PPAR&gamma; 10 SNPs genotype analysis. Logistic regression model was used to examine the association between 10 SNPs in the PPARs and non-HDL-C. Interactions within the 10 SNP were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR).

RESULTSA total of 820 participants (mean age was 50.05±9.41) were included in the study and 270 were males and 550 were females. Single-locus analysis showed that after adjusting gender, age, smoking, alcohol consumption, physical activity, high-fat diet and low-fiber diet factors, rs1800206-V and rs3856806-T were significantly associated with higher non-HDL-C levels. V allele (LV + VV genotype) carriers of rs1800206 have a average non-HDL-C levels on (3.15 ± 0.89)mg/L (F = 15.01, P = 0.002); T allele (CT+TT genotype) carriers of rs3856806 have a average non-HDL-C levels on (3.03±1.01) mg/L (F = 9.87, P = 0.005). GMDR model analysis showed that after adjusting the same factors, two-locus model, five-locus model, six-locus model and seven-order interaction models were all statistically significant (P<0.05), and the seven-locus model (rs1800206, rs3856806, rs135539, rs4253778, rs2016520, rs1805192, rs709158) was the best model (P = 0.001), the cross-validation consistency was 10/10 and testing accuracy was 0.656.

CONCLUSIONRs1800206 and rs3856806 were significantly associated with non-HDL-C. And there was an gene-gene interaction among rs1800206, rs3856806, rs1800206, rs135539, rs4253778, rs2016520, rs1805192, rs3856806 and rs709158 which could influence the non-HDL-C levels.

Alleles ; Cardiovascular Diseases ; Cholesterol ; Diabetes Mellitus, Type 2 ; Female ; Genetic Phenomena ; Genotype ; Humans ; Logistic Models ; Male ; Middle Aged ; Overweight ; PPAR alpha ; PPAR delta ; PPAR gamma ; Peroxisome Proliferator-Activated Receptors ; Polymorphism, Single Nucleotide ; Stroke

PURPOSE: This study was intended to establish experimental conditions for monitoring the cardioprotective effects of fenofibrate on cardiac function in lipopolysaccharide (LPS)-stimulated BalB/c mice. METHODS: To investigate the effects of fenofibrate on cardiac function, expression of Peroxisome proliferator-activated receptors (PPARs) and Peroxisome proliferator-activated receptor Gamma coactivator 1(PGC-1) and its target gene in the heart tissues of mice was compared after controls and LPS injection with pretreated fenofibrate or alone using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot analysis, and immunohistochemistry. In addition, Enzyme-linked-immunosorbent-assays (ELISA) were performed for assessment of pro-inflammatory cytokines of blood serum. RESULTS: Pretreated with fenofibrate had protective effects of diminishing the levels of LPS-induced pro-inflammatory cytokines, including interleukin-1beta (IL-1beta), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) and recovery from reduction of messenger Ribo-nucleic acid, protein level of PPARs and PGC-1 in LPS-administered heart tissue. In addition, increasing expression of PPARs and PGC-1 ameliorated the expression and activity of catalase blocked production of lipid peroxidation. CONCLUSION: Treatment with fenofibrate resulted in augmented expression of transcription factors and reduced production of pro-inflammatory cytokines and lipid peroxidation after LPS administration. Therefore, results of this study suggested that fenofibrate should not only have a protective effect but should also restore cardiac function in several cardiac dysfunctional situations.
Animals ; Blotting, Western ; Catalase ; Cytokines ; Fenofibrate ; Heart ; Immunohistochemistry ; Interleukin-1beta ; Interleukin-6 ; Lipid Peroxidation ; Mice ; Peroxisome Proliferator-Activated Receptors ; PPAR gamma ; Sepsis ; Transcription Factors ; Tumor Necrosis Factor-alpha

We determined the effects of dietary manipulations on messenger RNA of peroxisome proliferators activated receptor isoforms (i.e., PPAR alpha, beta/delta, gamma)in red vastus lateralis muscle of rats. Total 16 male Sprague-Dawley rats were used, and animals were divided into one of two dietary conditions :either chow diet group (CHOW ;n =8 )in which animals were fed with standard rodent chow (61.8% carbohydrate, 15.7% fat, 22.5% protein )or high fat diet group (FAT n =8 ) in which animals were fed 24.3% carbohydrate, 52.8% fat, 22.9% protein. At the end of the 8 weeks of experimental pe-riod, red vastus lateralis muscle was dissected out from all animals, and PPAR alpha, beta/delta, gamma mRNA expression was deter-mined. There was no significant difference in body mass (BM )between CHOW and FAT. As expected, blood glucose and free fatty acid (FFA )concentration was higher in FAT than CHOW (p <0.05 ), and lactate concentration was significan-tly lower in FAT compared to CHOW (p <0.05 ). Insulin concentration tended to higher in FAT than CHOW (67.2 +/- 21.9 vs. 27.0 +/-5.2 pmol/L ), but it did not reach to the statistical significance. Gene expression of PPAR alpha was not signifi-cantly different between CHOW and FAT. It was not also significantly different in PPAR beta/delta. Interestingly, expression of mRNA in PPAR gamma however, was markedly depressed in FAT compared to CHOW (approximately 3 fold higher in CHOW ; p <0.05 ). Results obtained from present study implies that PPAR gamma (as compensatory function of PPAR alpha is expressed ) possibly exerts another major tuning roles in fatty acid transport, utilization, as well as biosynthesis in skeletal muscle cells. The situations and conditions that can be postulated for this implication need to be further examined.
Animals ; Blood Glucose ; Diet ; Diet, High-Fat ; Gene Expression ; Humans ; Insulin ; Lactic Acid ; Male ; Muscle, Skeletal* ; Peroxisome Proliferator-Activated Receptors ; Peroxisome Proliferators ; Peroxisomes* ; PPAR alpha ; PPAR gamma ; Protein Isoforms* ; Quadriceps Muscle ; Rats* ; Rats, Sprague-Dawley ; RNA, Messenger* ; Rodentia

OBJECTIVE: Genetic variation in the serotonin-2C receptor encoded by the HTR2C gene is one of the genetic determinants of antipsychotic-induced weight gain. Peroxisome proliferator-activated receptors are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. In this cross-sectional study, we investigated whether HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T genotypes were associated with metabolic syndrome (MetS) in patients with schizophrenia taking clozapine. METHODS: One hundred forty-six Korean patients using clozapine for more than one year were genotyped for the HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T polymorphisms, and their weight, waist circumference, blood pressure, triglycerides, high-density lipoprotein-cholesterol, total cholesterol, and glucose were measured. We used the criteria for MetS proposed by the National Cholesterol Education Program-adapted Adult Treatment Panel III. RESULTS: The prevalence of MetS was 47.3% and was similar among men (49%) and women (42.9%). We found no significant differences between patients with and without MetS in terms of genotypes or allele frequencies. Logistic regression analyses also revealed no association between MetS and each genotype. CONCLUSION: We did not find significant associations between four polymorphisms (HTR2C-759C/T, HTR2C-697G/C, PPARalpha V227A, and PPARgamma 161C/T) and MetS in patients with schizophrenia taking clozapine.
Adult ; Blood Pressure ; Cholesterol ; Clozapine ; Cross-Sectional Studies ; Female ; Gene Frequency ; Genetic Variation ; Genotype ; Glucose ; Humans ; Logistic Models ; Male ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes ; Polymorphism, Genetic ; PPAR alpha ; PPAR gamma ; Prevalence ; Receptors, Cytoplasmic and Nuclear ; Schizophrenia ; Triglycerides ; Waist Circumference ; Weight Gain

Natural T-Regulatory (nTreg) cells represent approximately 8-10% of the total CD4+ T cell population and constantly expressing Foxp3 proteins. These cells are crucial for immune homeostasis, preventing over-inflammation and autoimmunity. Our previous study reported that PPAR&gamma; ligand, 15d-PGJ2 negatively influences the expression of Foxp3 in nTreg cells, which reflexes the attenuation in immunosuppressive function of nTreg cells. This study aims to unveil the molecular mechanism of Foxp3 suppression by PPAR&gamma; in nTreg cells during autoimmune Type 1 Diabetes. Co-stimulatory proteins were measured using flow cytometry and methylation measurement of Foxp3 expression was measured based on histone modification activity. Nuclear proteins of isolated cells were extracted out to measure two HDAC and two HAT enzyme activities using ELISA. Purified nTreg cells were isolated using MoFlow Cell sorter, and will be then cultured for 72 hrs to mimic the TCR activation and downstream signalling. The expression of Foxp3 in these cells were measured using flow cytometry analysis and were positively selected. Current data showed that histone acetylation activities were cross talked with PPAR&gamma; pathway in nTreg cells from diabetic, but in healthy mice. FoxP3 gene expression may be regulated via histone modification that in diabetic mice via PPAR&gamma;- independent pathways. Altogether, this study provides fundamental analysis on the putative role of PPAR&gamma; ligand 15d-PGJ2 as HDAC6/11 inhibitors. Therefore, this may suggest that combination of 15d-PGJ2 and GW9662 can be an alternative to HDAC6 inhibitor which is less toxic compared to pan-HDACi in treating inflammatory-related diseases. These ligands also potentially able to suppress the microenvironment of nTreg cells protecting tumour-bearing cells.
Peroxisome Proliferator-Activated Receptors

A series of novel tetrahydrocarboline derivatives was designed and synthesized in order to discover more potent peroxisome proliferator-activated receptor (PPAR) alpha/gamma dual regulators. The structures of these compounds were confirmed by 1H NMR and HR-MS; their PPAR-regulating activities were evaluated in vitro. Compounds 6h, 6n, 6p and 6q exhibited more potent PPARalpha agonistic activities than the control drug WY14643, while compounds 60, 6g, 6i and 6q exhibited more potent PPARgamma agonistic activities than the control drug rosiglitazone. Compound 6q was discovered as a potent PPARalpha/gamma dual agonist and deserves further investigation.
Animals ; Carbolines ; chemical synthesis ; chemistry ; pharmacology ; Cells, Cultured ; Drug Design ; Hypoglycemic Agents ; chemical synthesis ; chemistry ; pharmacology ; Molecular Structure ; PPAR alpha ; agonists ; PPAR gamma ; agonists ; Peroxisome Proliferator-Activated Receptors ; agonists ; Pyrimidines ; metabolism ; Structure-Activity Relationship ; Thiazolidinediones ; metabolism ; Transfection

PURPOSE: To evaluate whether factors related to lipid and glucose metabolism have a potential role in the progression of prostate cancer, we measured the mRNA levels of the peroxisome proliferator-activated receptor (PPAR), fatty acid elongase (ELOVL), and two glycolytic enzymes in prostate cancer (CaP) tissues. MATERIALS AND METHODS: Prostate tissues, obtained from radical prostatectomy (n=10) and transurethral resection of prostate (n=18), were quickly frozen in liquid nitrogen for RNA measurements. Transcript signals of PPAR alpha, PPAR gamma, ELOVL2, ELOVL5, phosphoglycerate kinase 1 (PgK1) and phosphoglycerate mutase 2 (PgM2) were measured using a reverse-transcription polymerase chain reaction. RESULTS: The transcript signals of PPAR alpha and PPAR gamma were down-regulated in CaP tissues. In addition, the mRNA level of PgM2 in CaP tissues was lower than that in benign prostatic hyperplasia (BPH) tissues. However, the messages for ELOVL2, ELOVL5, and PgK1 were not significantly changed. CONCLUSIONS: These results suggest that lowering of the PPARalpha, PPARgamma and PgM2 messages may be involved in aberrant and uncontrolled prostate cell growth and differentiation.
Down-Regulation* ; Glucose ; Metabolism ; Nitrogen ; Peroxisome Proliferator-Activated Receptors ; Peroxisomes* ; Phosphoglycerate Kinase ; Phosphoglycerate Mutase* ; Polymerase Chain Reaction ; PPAR alpha ; PPAR gamma* ; Prostate* ; Prostatectomy ; Prostatic Hyperplasia ; Prostatic Neoplasms* ; RNA ; RNA, Messenger ; Transurethral Resection of Prostate

BACKGROUNDThe chronic pathological changes in vascular walls of hypertension may exert destructive effects on multiple organ systems. Accumulating evidence indicates that inflammatory reactions are involved in the pathological changes of hypertension. Three peroxisome proliferator-activated receptors (PPARs) have been identified: PPARalpha, PPARbeta/delta, and PPARgamma, all of which have multiple biological effects, especially the inhibition of inflammation. The aim of this study was to evaluate PPAR isoforms expression profile in important organs of spontaneously hypertensive rats (SHR) and to understand the modulation of endogenous PPAR isoforms under inflammatory condition.

METHODSTissues (kidney, liver, heart, and brain) were dissected from SHR and age-matched control Wistar-Kyoto rats (WKY) to investigate the abundance of PPAR isoforms and PPAR-responsive genes (acyl-CoA oxidase and CD36). The expression of CCAAT/enhancer-binding protein delta (C/EBPdelta), which can trans-activate PPARgamma expression, was also observed. The inflammatory response was analyzed by the expression of inflammatory mediators inducible nitric oxide synthase (iNOS), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), E-selectin, interleukin-1 beta (IL-1beta), and tumor necrosis factor alpha (TNFalpha), and formation of carbonyl and nitrated proteins.

RESULTSThe expressions of 3 PPAR isoforms and PPAR-responsive genes were markedly upregulated in SHR compared with those of WKY. Specifically, the expression of PPARalpha protein in the kidney, liver, heart and brain increased by 130.76%, 91.48%, 306.24%, and 90.70%; PPARbeta/delta upregulated by 109.34%, 161.98%, 137.04%, and 131.66%; PPARgamma increased by 393.76%, 193.17%, 559.29%, and 591.18%. In consistent with the changes in PPARgamma, the expression of C/EBPdelta was also dramatically elevated in SHR. Inflammatory mediators expressions were significantly increased in the most organs of SHR than WKY. As a consequence, increased formation of carbonyl and nitrated proteins were also observed in the most organs of SHR.

CONCLUSIONSThese findings suggest an enhanced inflammatory response in the organs of SHR, which might play a key role in pathogenesis of hypertension and secondary organ complications. Changes (increases) in PPARs expression may reflect a compensatory mechanism to the inflammatory status of hypertensive rats.

Animals ; Blood Pressure ; Blotting, Western ; E-Selectin ; genetics ; metabolism ; Gene Expression ; Hypertension ; genetics ; metabolism ; physiopathology ; Inflammation ; genetics ; metabolism ; physiopathology ; Interleukin-1beta ; genetics ; metabolism ; Male ; PPAR alpha ; genetics ; metabolism ; PPAR delta ; genetics ; metabolism ; PPAR gamma ; genetics ; metabolism ; Peroxisome Proliferator-Activated Receptors ; genetics ; metabolism ; Plethysmography ; methods ; Rats ; Rats, Inbred SHR ; Rats, Inbred WKY ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Necrosis Factor-alpha ; genetics ; metabolism ; Vascular Cell Adhesion Molecule-1 ; genetics ; metabolism

Dental pulp is a loose, mesenchymal tissue almost entirely enclosed in the dentin. It consists of cells, ground substance, and neural and vascular supplies. Damage to the dental pulp by mechanical, chemical, thermal, and microbial irritants can provoke various types of inflammatory response. Pulpal inflammation leads to the tissue degradation, which is mediated in part by Matrix metalloproteinase leads to accelerate extracellular matrix degradation with pathological pathway. We have now investigated the induction of MMPs and inflammatory cytokines by Lipopolysaccharide (LPS) control of inflammatory mediators by peroxisome proliferator-activated receptors (PPARs). Human dental pulp cells exposed to various concentrations of LPS (1-10 microg/ml) revealed elevated levels of MMP-2 and MMP-9 at 24 hrs of culture. LPS also stimulated the production of ICAM-1, VCAM-1, IL-1beta, and TNF-alpha. Adenovirus PPARgamma (Ad/PPARgamma) and PPARgamma agonist rosiglitazone reduced the synthesis of MMPs, adhesion molecules and pro-inflammatory cytokines. The inhibitory effect of Ad/PPARgamma was higher than that of PPARgamma agonist. These result offer new insights in regard to the anti-inflammatory potential of PPARgamma in human dental pulp cell.
Adenoviridae ; Cytokines ; Dental Pulp* ; Dentin ; Equipment and Supplies ; Extracellular Matrix ; Humans* ; Inflammation ; Intercellular Adhesion Molecule-1 ; Irritants ; Matrix Metalloproteinases ; Peroxisome Proliferator-Activated Receptors ; PPAR gamma* ; Tumor Necrosis Factor-alpha ; Vascular Cell Adhesion Molecule-1