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1.
Article in Chinese | WPRIM | ID: wpr-773155

ABSTRACT

Tanshinone Ⅱ_A( Tan Ⅱ_A),the liposoluble constituents of Salvia miltiorrhiza,can not only ameliorate the lipidic metabolism and decrease the concentration of lipid peroxidation,but also resist oxidation damage,scavenge free radicals and control inflammation,with a protective effect on prognosis after liver function impairment. Therefore,the studies on the exact mechanism of Tan Ⅱ_A in protecting the liver can provide important theoretical and experimental basis for the prevention and treatment effect of Tan Ⅱ_A for liver injury. In the present study,the protective effects and mechanism of Tan Ⅱ_A on 4-hydroxynonenal( 4-HNE)-induced liver injury were investigated in vitro. Normal liver tissues NCTC 1469 cells were used to induce hepatocytes oxidative damages by 4-HNE treatment. The protective effect of Tan Ⅱ_A on hepatocytes oxidative damages was detected by release amount of lactate dehydrogenase( LDH) analysis and hoechst staining. The protein expression changes of peroxisome proliferator-activated receptor α( PPARα) and peroxisome proliferator response element( PPRE) were analyzed by Western blot analysis in NCTC 1469 cells before and after Tan Ⅱ_A treatment. The gene expression changes of fatty aldehyde dehydrogenase( FALDH) were analyzed by Real-time polymerase chain reaction( PCR) analysis. The results showed that 4-HNE increased the release amount of LDH,lowered the cell viability of NCTC 1469 cells,and Tan Ⅱ_A reversed 4-HNE-induced hepatocyte damage. Western blot analysis and RT-PCR analysis results showed that 4-HNE decreased the expression of PPARα and FALDH and increased the expression of 4-HNE. However,the expression of PPARα and FALDH were increased significantly and the expression of 4-HNE was decreased obviously after Tan Ⅱ_A treatment. This study confirmed that the curative effect of Tan Ⅱ_A was obvious on hepatocytes damage,and the mechanism may be associated with activating PPARα and FALDH expression as well as scavenging 4-HNE.


Subject(s)
Aldehyde Oxidoreductases , Metabolism , Aldehydes , Animals , Cell Line , Abietanes , Pharmacology , Hepatocytes , Lipid Peroxidation , Mice , Oxidative Stress , PPAR alpha , Metabolism
2.
Article in English | WPRIM | ID: wpr-777594

ABSTRACT

The plasticizer di(2-ethylhexyl) phthalate (DEHP) has been widely used in the manufacture of polyvinyl chloride-containing products such as medical and consumer goods. Humans can easily be exposed to it because DEHP is ubiquitous in the environment. Recent research on the adverse effects of DEHP has focused on reproductive and developmental toxicity in rodents and/or humans. DEHP is a representative of the peroxisome proliferators. Therefore, peroxisome proliferator-activated receptor alpha (PPARα)-dependent pathways are the expected mode of action of several kinds of DEHP-induced toxicities. In this review, we summarize DEHP kinetics and its mechanisms of carcinogenicity and reproductive and developmental toxicity in relation to PPARα. Additionally, we give an overview of the impacts of science policy on exposure sources.


Subject(s)
Animals , Diethylhexyl Phthalate , Toxicity , Environmental Pollutants , Toxicity , Haplorhini , Humans , Mice , PPAR alpha , Genetics , Metabolism , Plasticizers , Toxicity , Rats
3.
Article in English | WPRIM | ID: wpr-760620

ABSTRACT

BACKGROUND/OBJECTIVES: Docosahexaenoic acid (DHA), an n-3 long chain polyunsaturated fatty acid (LCPUFA), is acquired by dietary intake or the in vivo conversion of α-linolenic acid. Many enzymes participating in LCPUFA synthesis are regulated by peroxisome proliferator-activated receptor alpha (PPARα). Therefore, it was hypothesized that the tissue accretion of endogenously synthesized DHA could be modified by PPARα. MATERIALS/METHODS: The tissue DHA concentrations and mRNA levels of genes participating in DHA biosynthesis were compared among PPARα homozygous (KO), heterozygous (HZ), and wild type (WT) mice (Exp I), and between WT mice treated with clofibrate (PPARα agonist) or those not treated (Exp II). In ExpII, the expression levels of the proteins associated with DHA function in the brain cortex and retina were also measured. An n3-PUFA depleted/replenished regimen was applied to mitigate the confounding effects of maternal DHA. RESULTS: PPARα ablation reduced the hepatic Acox, Fads1, and Fads2 mRNA levels, as well as the DHA concentration in the liver, but not in the brain cortex. In contrast, PPARα activation increased hepatic Acox, Fads1, Fads2 and Elovl5 mRNA levels, but reduced the DHA concentrations in the liver, retina, and phospholipid of brain cortex, and decreased mRNA and protein levels of the brain-derived neurotrophic factor in brain cortex. CONCLUSIONS: LCPUFA enzyme expression was altered by PPARα. Either PPARα deficiency or activation-decreased tissue DHA concentration is a stimulus for further studies to determine the functional significance.


Subject(s)
Animals , Brain , Brain-Derived Neurotrophic Factor , Clofibrate , Docosahexaenoic Acids , Fatty Acid Desaturases , Liver , Mice , Peroxisomes , PPAR alpha , Retina , RNA, Messenger
4.
Korean Circulation Journal ; : 1097-1119, 2018.
Article in English | WPRIM | ID: wpr-738672

ABSTRACT

Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.


Subject(s)
Apolipoprotein C-III , Cardiovascular Diseases , Diacylglycerol O-Acyltransferase , Fatty Acids, Omega-3 , Fibric Acids , Hyperlipoproteinemia Type I , Life Style , Lipase , Lipoprotein Lipase , Lipoproteins , Metabolism , Mortality , PPAR alpha , Risk Factors , Triglycerides
5.
Clinics ; 71(3): 163-168, Mar. 2016. tab, graf
Article in English | LILACS | ID: lil-778995

ABSTRACT

OBJECTIVE: Exercise is a protective factor for cardiovascular morbidity and mortality, with unclear mechanisms. Changing the myocardial metabolism causes harmful consequences for heart function and exercise contributes to metabolic adjustment modulation. Peroxisome proliferator-activated receptors (PPARs) are also myocardium metabolism regulators capable of decreasing the inflammatory response. We hypothesized that PPAR-α is involved in the beneficial effects of previous exercise on myocardial infarction (MI) and cardiac function, changing the expression of metabolic and inflammatory response regulators and reducing myocardial apoptosis, which partially explains the better outcome. METHODS AND RESULTS: Exercised rats engaged in swimming sessions for 60 min/day, 5 days/week, for 8 weeks. Both the exercised rats and sedentary rats were randomized to MI surgery and followed for 1 week (EI1 or SI1) or 4 weeks (EI4 or SI4) of healing or to sham groups. Echocardiography was employed to detect left ventricular function and the infarct size. Additionally, the TUNEL technique was used to assess apoptosis and immunohistochemistry was used to quantitatively analyze the PPAR-α, TNF-α and NF-κB antigens in the infarcted and non-infarcted myocardium. MI-related mortality was higher in SI4 than in EI4 (25% vs 12%), without a difference in MI size. SI4 exhibited a lower shortening fraction than EI4 did (24% vs 35%) and a higher apoptosis/area rate (3.97±0.61 vs 1.90±1.82) in infarcted areas (both p=0.001). Immunohistochemistry also revealed higher TNF-α levels in SI1 than in EI1 (9.59 vs 4.09, p<0.001) in infarcted areas. In non-infarcted areas, EI4 showed higher levels of TNF-α and positive correlations between PPAR-α and NF-κB (r=0.75, p=0.02), in contrast to SI4 (r=0.05, p=0.87). CONCLUSION: Previously exercised animals had better long-term ventricular function post-MI, in addition to lower levels of local inflammatory markers and less myocardial apoptosis, which seemed to be related to the presence of PPAR-α.


Subject(s)
Animals , Female , Myocardial Infarction/metabolism , PPAR alpha/metabolism , Physical Conditioning, Animal/physiology , Apoptosis/physiology , Inflammation/metabolism , Models, Animal , Myocardial Infarction/pathology , Myocardial Infarction , NF-kappa B/metabolism , PPAR alpha/analysis , Random Allocation , Rats, Wistar , Time , Tumor Necrosis Factor-alpha/metabolism , Ventricular Function/physiology
6.
Article in Chinese | WPRIM | ID: wpr-289890

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the roles of microRNA-21 (miR-21) in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) with high-fat diet-induced insulin resistance (IR) and diabetes mellitus (DM) mice model.</p><p><b>METHODS</b>Eight-week-old C57BL/6 mice were allocated into control group, IR group, and DM group. Body mass was recorded. Intraperitoneal glucose tolerance test was performed to determine any abnormal glucose metabolism. The liver pathological changes were detected by biopsy. Changes in free blood glucose, free serum insulin, blood fat and tumor necrosis factor Α level were measured. Differences in miR-21 expression and peroxidase proliferator-activated receptor subtypes (PPAR-Γ and PPAR-Α) and adipocyte fatty acid binding protein (aP2) in the liver were detected both at the mRNA and protein levels.</p><p><b>RESULTS</b>After one 8-week high-fat diet, the body mass, free serum insulin, and homeostasis model IR index significantly increased in the IR group (P<0.01, P<0.05, compared with control group), while the free blood glucose increased and the free serum insulin decreased in DM group (P<0.05). Free serum insulin level were significantly increased in IR group (P<0.05). Serum tumor necrosis factor-Α levels exhibited an upward trend in control group, IR group, and DM group (P<0.05, P<0.01). With exacerbation in NAFLD, liver miR-21 expression level went further down in both IR and DM groups (P<0.05). The downregulated miR-21 expression level showed negative correlation with upregulated PPAR-Α, ΑP2, and PPAR-Γ genetic expression (r=-0.696, r=-0.664, and r=-0.766, respectively; P<0.05) in IR group and with upregulated PPAR-Α and PPAR-Γ genetic expression in DM group (r=-0.676 and r=-0.550, respectively; P<0.05). In terms of the changes in protein expression level,only on the protein expressions of aP2 and PPAR-Γ in IR group showed significant change (P<0.05, P<0.01, compared with control group).</p><p><b>CONCLUSIONS</b>The miR-21 expression is downregulated in both IR and DM-induced NAFLD mice. It may be involved in the pathogenesis of NAFLD by regulating the expressions of PPAR subtypes.</p>


Subject(s)
Animals , Blood Glucose , Diabetes Mellitus, Experimental , Diet, High-Fat , Disease Models, Animal , Insulin , Blood , Insulin Resistance , Mice , Mice, Inbred C57BL , MicroRNAs , Metabolism , Non-alcoholic Fatty Liver Disease , PPAR alpha , Metabolism , PPAR gamma , Metabolism , Tumor Necrosis Factor-alpha , Metabolism
7.
Clinics ; 70(12): 790-796, Dec. 2015. tab, graf
Article in English | LILACS | ID: lil-769706

ABSTRACT

OBJECTIVE: To determine peroxisome proliferator activated receptor α and γ mRNA expression in liver tissue of hepatitis C virus-infected patients with and without human immunodeficiency virus and its possible contribution to an acceleration of liver disease progression. METHODS: We measured peroxisome proliferator-activated receptor α and γ mRNA expression by real-time polymerase chain reaction in liver tissues from 40 subjects infected only with hepatitis C virus, 36 subjects co-infected with hepatitis C virus and human immunodeficiency virus and 11 normal adults. RESULTS: Hepatic mRNA expression of both peroxisome proliferator-activated receptors was significantly lower in hepatitis C virus-infected subjects with and without human immunodeficiency virus co-infection compared to the controls. Non-black race was also identified as a predictor of lower peroxisome receptor α and γ mRNA expression. Compared to subjects infected only with hepatitis C virus, liver peroxisome receptor γ mRNA expression was significantly lower in hepatitis C virus/human immunodeficiency virus-co-infected subjects (0.0092 in hepatitis C virus/human immunodeficiency virus-co-infection vs. 0.0120 in hepatitis C virus-only; p=0.004). Hepatic peroxisome receptor α mRNA expression in the hepatitis C virus-infected patients was lower in the presence of human immunodeficiency virus co-infection in non-black subjects (0.0769 vs. 0.1061; p=0.02), whereas the levels did not vary based on human immunodeficiency virus status among black subjects. CONCLUSION: mRNA expression of both peroxisome proliferator-activated receptors is impaired in hepatitis C virus-infected liver and further reduced by human immunodeficiency virus co-infection, although the suppressive effects of the viruses are substantially mitigated in black patients.


Subject(s)
Adult , Aged , Female , Humans , Male , Middle Aged , Coinfection/pathology , HIV Infections/pathology , Hepatitis C, Chronic/pathology , PPAR alpha/analysis , PPAR gamma/analysis , RNA, Messenger/analysis , Analysis of Variance , Biopsy , Cross-Sectional Studies , Coinfection/complications , Coinfection/ethnology , HIV Infections/complications , HIV Infections/ethnology , Hepatitis C, Chronic/complications , Hepatitis C, Chronic/ethnology , Linear Models , Liver Cirrhosis/etiology , Liver Cirrhosis/pathology , Liver/pathology , PPAR alpha/genetics , PPAR gamma/genetics , Real-Time Polymerase Chain Reaction , Reference Values , Severity of Illness Index
8.
Article in Chinese | WPRIM | ID: wpr-255152

ABSTRACT

<p><b>OBJECTIVE</b>To detect the expression of the plateau adaptablity gene(EPAS1, EGLN1 and PPARα) and proteins(HIF-2, PHD2 and PPARα) in rats blood, heart, liver, lung and kidney tissue after the rats exposed to high altitude.</p><p><b>METHODS</b>The Wistar rats were randomly divided into plain group(Shanghai, 55 m), acute exposure to high altitude 3400 m group, acute exposure to high altitude 4300 m group. Blood and organs of rats were collected in 1, 3, 5 days after arrival. Real time PCR and ELISA were used to compare the expression of plateau adaptablity gene and related protein between plain group and high altitude exposure groups.</p><p><b>RESULTS</b>The count of red blood cells, hemoglobin and HCT in high altitude 4300 m were higher than those in plain group. Compared with plain group, the expression of EPAS1 gene in blood, heart, liver and kidney tissue of rats at high altitude increased obviously(all P<0.05); the expression of EGLN1 in the heart, liver, brain and kidney increased, and PPARα gene in the heart, liver and kidney increased(all P<0.05). Compared with plain group, the expression of HIF-2 protein increased significantly at high altitudes in the liver, brain and kidney tissues. PHD2 and PPARα increased in the heart, liver and kidney.</p><p><b>CONCLUSION</b>Plateau adaptive genes(EPAS1, EGLN1 and PPARα) and protein(HIF-2, PHD2 and PPARα) differed in different altitude and different organizations. They might be used as target markers of plateau hypoxia.</p>


Subject(s)
Adaptation, Physiological , Altitude , Animals , Basic Helix-Loop-Helix Transcription Factors , Metabolism , Brain , China , Heart , Hypoxia , Hypoxia-Inducible Factor-Proline Dioxygenases , Metabolism , Kidney , Liver , Lung , PPAR alpha , Metabolism , Procollagen-Proline Dioxygenase , Metabolism , Rats , Rats, Wistar
9.
Article in Chinese | WPRIM | ID: wpr-255030

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect of peroxisiome proliferator activated receptor-α (PPAR-α) on the regulation of cardiomyocyte hypertrophy and the relationship between the effect of PPAR-α with PI3K/Akt//mTOR signal pathway.</p><p><b>METHODS</b>Cardiomyocyte hypertrophy was induced by isoproterenol (ISO). The cell surface area was measured by image analysis system (Leica). The expressions of atrial natriuretic peptide (ANP), β-myosin heavy chain (β-MHC) and PPAR-α mRNA were detected by qRT-PCR. The protein expressions of Akt, mTOR and P70S6K were detected by Western blot. The expression of PPAR-α was suppressed by RNAi.</p><p><b>RESULTS</b>(1) The expression of PPAR-α was significantly reduced in cardiomyocyte hypertrophy. PPAR-α activator Fenofibrate (Feno) increased the expression of PPAR-α and suppressed cardiomyocyte hypertrophy. The inhibitory effect of Feno on cardiomyocyte hypertrophy was reversed by PPAR-α RNAi. (2) Feno significantly inhibited the increase of the protein expressions of p-Akt, p-mTOR and p-p70S6K in ISO induced cardiomyocyte hypertrophy, which could be blocked by PPAR-α RNAi. (3) PI3K antagonist LY294002 (LY) or mTOR antagonist rapamycin (RAPA) markedly-inhibited cardiomyocyte hypertrophy. The inhibitory effects of LY or RAPA on cardiomyocyte hypertrophy were reversed by PPAR-α RNAi.</p><p><b>CONCLUSION</b>PPAR-α can negatively regulate cardiomyocyte hypertrophy. The effect might be associated with PPAR-α inhiting PI3K/ Akt/mTOR signal pathway.</p>


Subject(s)
Atrial Natriuretic Factor , Metabolism , Cardiomegaly , Metabolism , Cells, Cultured , Fenofibrate , Pharmacology , Humans , Isoproterenol , Myocytes, Cardiac , Metabolism , Myosin Heavy Chains , Metabolism , PPAR alpha , Metabolism , Phosphatidylinositol 3-Kinases , Metabolism , Proto-Oncogene Proteins c-akt , Metabolism , RNA, Messenger , Ribosomal Protein S6 Kinases, 70-kDa , Metabolism , Signal Transduction , TOR Serine-Threonine Kinases , Metabolism
10.
Article in Chinese | WPRIM | ID: wpr-337919

ABSTRACT

Traditional Chinese medicine (TCM) has definitely clinical effect in treating hyperlipidemia, but the action mechanism still need to be explored. Based on consulting Chinese Pharmacopoeia (2010), all the lipid-lowering Chinese patent medicines were analyzed by associated rules data mining method to explore high frequency herb pairs. The top three couplet medicines with high support degree were Puerariae Lobatae Radix-Crataegi Fructus, Salviae Miltiorrhizae Radix et Rhizoma-Crataegi Fructus, and Polygoni Multiflori Radix-Crataegi Fructus. The 20 main ingredients were selected from the herb pairs and docked with 3 key hyperlipidemia targets, namely 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), peroxisome proliferator activated receptor-α (PPAR-α ) and niemann-pick C1 like 1 (NPC1L1) to further discuss the molecular mechanism of the high frequency herb pairs, by using the docking program, LibDock. To construct evaluation rules for the ingredients of herb pairs, the root-mean-square deviation (RMSD) value between computed and initial complexes was first calculated to validate the fitness of LibDock models. Then, the key residues were also confirmed by analyzing the interactions of those 3 proteins and corresponding marketed drugs. The docking results showed that hyperin, puerarin, salvianolic acid A and polydatin can interact with two targets, and the other five compounds may be potent for at least one of the three targets. In this study, the multi-target effect of high frequency herb pairs for lipid-lowering was discussed on the molecular level, which can help further researching new multi-target anti-hyperlipidemia drug.


Subject(s)
Asteraceae , Chemistry , Drugs, Chinese Herbal , Chemistry , Metabolism , Humans , Hydroxymethylglutaryl CoA Reductases , Chemistry , Genetics , Metabolism , Hyperlipidemias , Drug Therapy , Genetics , Metabolism , Hypolipidemic Agents , Chemistry , Metabolism , Membrane Proteins , Chemistry , Genetics , Metabolism , Molecular Docking Simulation , PPAR alpha , Chemistry , Genetics , Metabolism , Protein Binding , Pueraria , Chemistry
11.
Chinese Journal of Hepatology ; (12): 124-129, 2015.
Article in Chinese | WPRIM | ID: wpr-337027

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the effect of apigenin on the protein expression levels of peroxisome proliferator-activated receptors (PPARs) in liver tissues of rats with nonalcoholic steatohepatitis (NASH).</p><p><b>METHODS</b>The NASH rat model was established by feeding of a high-fat diet. Unmodeled rats served as the normal controls. The modeled rats were divided into a model control group, Essentiale treatment grouP(300 mg/kg/day),and three apigenin treatment groups for low-dose (15 mg/kg/day), moderate-dose (30 mg/kg/day) and high-dose (60 mg/kg/day). After 13 weeks of treatment,changes in insulin sensitivity from pre-treatment baseline were assessed by measuring the alanine aminotransferase (ALT), aspartate aminotransferase (AST),total cholesterol (TC),triglycerides (TG),low-density and high-density lipoprotein cholesterol (LDL-C and HDL-C),fasting blood glucose (FBG) and fasting insulin (FINS).The liver index and HOMA-IR were also calculated.Protein and gene expression of PPARα and PPARgamma in liver tissue were assessed by immunohistochemistry and RT-PCR.Statistical analysis was performed by the LSD test and Games-Howell test.</p><p><b>RESULTS</b>The apigenin-treated groups showed a significantly greater change in insulin sensitivity than the untreated model group,with the most significant change occurring in the high-dose grouP(P less than 0.05).Compared with the untreated model group,the apigenin-treated groups showed lower levels of ALT (95.4+/-7.3),AST (183.7+/-14.3),TC (1.61+/-0.25),TG (1.23+/-0.21),LDL-C (1.86+/-0.14),FBG (5.29+/-1.45) and FINS (0.76+/-0.86),but a higher level of HDL-C (1.04+/-0.17); again,the high-dose group showed the greatest change (all P less than 0.05).Compared to the untreated model group,the apigenin-treated groups showed significantly lower liver index (3.75+/-0.25 vs.2.90+/-0.17) and HOMA-IR (1.34+/-0.06 vs.0.18+/-0.04),with the high-dose group showing the greatest change (both P less than 0.05). Compared to the untreated model group,the apigenin-treated groups showed higher levels of protein and mRNA of PPARα (18.27+/-4.05 and 0.63+/-0.02,respectively) and PPARgamma(8.48+/-5.05 and 0.39+/-0.02),with the high-dose group showing the greatest change (all P < 0.05).</p><p><b>CONCLUSION</b>Apigenin can improve glucose tolerance,lipid metabolism and insulin resistance while decreasing blood levels of TC,TG,LDL-C,FBG,FINS and HOMA-IR,and increasing HDL-C in NASH,as shown in a high-fat diet induced rat model, and may have therapeutic potential.</p>


Subject(s)
Alanine Transaminase , Metabolism , Animals , Apigenin , Pharmacology , Aspartate Aminotransferases , Metabolism , Blood Glucose , Metabolism , Cholesterol , Metabolism , Disease Models, Animal , Insulin , Metabolism , Insulin Resistance , Lipid Metabolism , Liver , Non-alcoholic Fatty Liver Disease , Metabolism , PPAR alpha , Metabolism , PPAR gamma , Metabolism , Peroxisome Proliferator-Activated Receptors , Metabolism , Rats , Rats, Sprague-Dawley , Triglycerides , Metabolism
12.
Article in Chinese | WPRIM | ID: wpr-291604

ABSTRACT

<p><b>OBJECTIVE</b>To 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.</p><p><b>METHODS</b>Participants 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 PPARα, PPARδ and PPARγ 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).</p><p><b>RESULTS</b>A 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.</p><p><b>CONCLUSION</b>Rs1800206 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.</p>


Subject(s)
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
13.
Chinese Journal of Cardiology ; (12): 328-333, 2015.
Article in Chinese | WPRIM | ID: wpr-328802

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARα, β, γ) with apolipoprotein A I/apolipoprotein B100 (ApoA I/ApoB100) ratio and the additional role of a gene-gene interactions among the 10 SNPs.</p><p><b>METHODS</b>Participants were recruited under the framework of the Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province (PMMJS) cohort population survey in the urban community of Jiangsu province of China.A total of 630 subjects were randomly selected and no individual was related.Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were selected from the HapMap database,which covered PPARα, PPARβ and PPARγ. A linear regression model was used to analyze the relations between ten SNPs in the PPARs and ApoA I/ApoB100 ratio level. Mean difference and 95% CI were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR).</p><p><b>RESULTS</b>After adjusting for age, gender, smoking status, alcohol consumption, occupational physical activity, high-fat diet as well as low-fiber diet, both rs1800206 and rs3856806 were significantly associated with a decreased level of ApoA I/ApoB100 ratio, mean difference (95% CI) values were -1.19 (-1.88 to -0.50) and -0.77 (-1.40 to -0.14). Whereas rs4253778 was significantly associated with an increased level of ApoA I/ApoB100 ratio, Mean difference (95% CI) values was 0.80 (0.08 to 1.52). GMDR analysis showed a significant gene-gene interaction among rs4253778, rs1800206 of PPARα, rs9794, rs2016520 of PPARβ and rs10865710, rs3856806, rs709158, rs1805192 of PPARγ for eight-dimension models (P = 0.01), in which prediction accuracy was 0.624 and cross-validation consistency was 7/10.</p><p><b>CONCLUSIONS</b>The rs1800206 of PPARα and rs3856806 of PPARγ are significantly associated with a decreased level of ApoA I/ApoB100 ratio while rs4253778 of PPARα is associated with an increased level of ApoA I/ApoB100 ratio. There is a gene-gene interaction between multiple SNPs.</p>


Subject(s)
Apolipoprotein A-I , Genetics , Apolipoprotein B-100 , Genetics , China , Diet, High-Fat , Epistasis, Genetic , Gene Frequency , Genotype , Humans , Metabolic Syndrome , PPAR alpha , Genetics , PPAR delta , PPAR gamma , Genetics , Polymorphism, Single Nucleotide
14.
Biol. Res ; 47: 1-9, 2014. ilus, graf
Article in English | LILACS | ID: biblio-950738

ABSTRACT

BACKGROUND: Tuberculosis (TB) is a respiratory tract disease caused by Mycobacterium tuberculosis infection. M. tuberculosis exploits immune privilege to grow and divide in pleural macrophages. Fibrates are associated with the immune response and control lipid metabolism through glycolysis with ß-oxidation of fatty acids. RESULTS: In this study, we investigated the effect of fibrate pretreatment on the immune response during M. smegmatis infection in U937 cells, a human leukemic monocyte lymphoma cell line. The protein expression of tumor necrosis factor α (TNF-α), an inflammatory marker, and myeloid differentiation primary response gene 88 (MyD88), a toll like receptor adaptor molecule, in the infected group increased at 1 and 6 h after M. smegmatis infection of U937 cells. Acetyl coenzyme A acetyl transferase-1 (ACAT-1), peroxisome proliferator-activated receptor-α (PPAR-α), TNF-α, and MyD88 decreased in U937 cells treated with fibrates at 12 and 24 h after treatment. More than a 24 h pretreatment with fibrate resulted in similar expression levels of ACAT-1 and PPAR-α between infected vehicle control and infected groups which were pretreated with fibrate for 24 h. However, upon exposure to M. smegmatis, the cellular expression of the TNF-α and MyD88 in the infected groups pretreated with fibrate for 24 h decreased significantly compared to that in the infected vehicle group. CONCLUSION: These results suggest that fibrate pretreatment normalized the levels of inflammatory molecules in Mycobacterium smegmatis-infected U937 cells. Further studies are needed to confirm the findings on pathophysiology and immune defense mechanism of U937 by fibrates during M. tuberculosis infection.


Subject(s)
Humans , Inflammation Mediators/metabolism , Mycobacterium smegmatis , Fibric Acids/pharmacology , Macrophages/drug effects , Mycobacterium Infections/metabolism , Acetyl-CoA C-Acetyltransferase/metabolism , Signal Transduction/drug effects , Blotting, Western , Tumor Necrosis Factor-alpha/metabolism , U937 Cells , PPAR alpha/metabolism , Myeloid Differentiation Factor 88/metabolism , Macrophages/metabolism , Macrophages/microbiology
15.
IJPM-International Journal of Preventive Medicine. 2014; 5 (3): 333-340
in English | IMEMR | ID: emr-141773

ABSTRACT

We determined the blood lipid-lowering effects of eicosapentaenoic acid [EPA] on hypertriglyceridemic subjects with Leu162/Val in exon 5 and G/C in intron7 polymorphism of peroxisome proliferator-activated receptor alpha [PPAR alpha]genotypes that, to our knowledge, have not been previously studied. A total of 170 hypertriglyceridemic subjects were enrolled and genotyped for Ala54Thr, Leu162Val, and intron 7 polymorphism by the use of a polymerase chain reaction restriction fragment length polymorphism method. After determination of their genotypes, the first 23 eligible subjects who were found as Ala54 carriers and the first 23 eligible Thr54 carriers were enrolled in the study and stratified for PPAR alpha genotypes. Participants took 2 g of pure EPA daily for 8 weeks. Fasting blood lipid and lipoprotein profiles were determined and changes from baseline were measured. We observed significant difference between EPA supplementation and Leu162 and Val162, Interon 7 [GG and GC] carriers [P < 0.001]. We did not observe significant associations between the PPAR alpha L162V single nucleotide polymorphism and multiple lipid and lipoprotein measures. Although EPA consumption lowered lipid and lipoprotein concentrations in Leu162 and Val162 carriers and Interon 7 CC and GC carriers, these differences between the studied groups were not statistically significant. EPA consumption has a lipid-lowering effect in hypertriglyceridemic subjects in both Leu162 and Val162 carriers. But there was no significant interaction between EPA supplementation and PPAR alpha genotypes. Thus, genetic variation within the PPAR alpha Leu162/Val cannot modulate the association of EPA intakes with lipid and lipoprotein profile. However, we must note that the sample size in this study was small


Subject(s)
Humans , Lipids , Lipoproteins , Hypertriglyceridemia , PPAR alpha , Genotype , Polymorphism, Genetic
16.
Iranian Journal of Public Health. 2014; 43 (6): 749-759
in English | IMEMR | ID: emr-167592

ABSTRACT

The peroxisome proliferator-activated receptors [PPARs] -alpha, -delta/beta and -gamma are the ligand-activated tran-scription factors involved in the regulation of fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation and atherosclerosis, etc. We investigated the associations of 10 single-nucleotide polymorphisms [SNPs] in PPARs with apolipoprotein [apo] A-I/ apoB ratio in Chinese Han population. Overall, 630 subjects [212 males, 418 females] were randomly selected from the Prevention of Metabolic Syndrome and Multiple Metabolic Disorders in Jiangsu Province of China Study Cohort. Population analyzed was as the general population which involved healthy people and individuals with disorders of apoA-I or apoB. 10 SNPs [rs1800206, rs135539, rs4253778, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847] were genotyped. Mean difference [Difference] and 95% confident interval [95%CI] were calculated. After covariates adjustment, rs1800206-V allele [LV+VV] and rs3856806-T allele [CT+TT] were significantly associated with a decreased apoA-I/ apoB ratio than those wild type carriers, Difference [95%CI] were -1.29[-1.96 tilde -0.62]and -0.8 [-1.42 tilde -0.17], respectively. Rs4253778-C allele was significantly associated with an increased apoA-I/ apoB ratio compared to the wild type carriers [GG], Difference [95%CI] was 0.76 [0.04 tilde 1.48]. Generalized multifactor dimensionality reduction analysis showed that three-to-eight-locus models were significant with apoA-I/ apoB ratio [P<0.05]. We chose the seven-locus model [P=0.0010] as the best GMDR model [cross-validation consistency was 7/10 and testing accuracy was 62.97%]. Our data provided the evidence that PPARs polymorphisms might be involved in regulation of apoA-I/ apoB ratio in independently and/or in an interactive manner


Subject(s)
Humans , Male , Female , PPAR alpha , PPAR delta , PPAR gamma , Apolipoproteins , Polymorphism, Single Nucleotide , Genes , Apolipoprotein A-I , Apolipoproteins B
17.
Article in Chinese | WPRIM | ID: wpr-254458

ABSTRACT

<p><b>OBJECTIVE</b>To study the expression of peroxisome proliferators-activated receptor (PPAR) in human glioma tissue and its influence on tumor growth.</p><p><b>METHODS</b>Expression of PPAR mRNA in glioma tissue was determined by real-time reverse transcription polymerase chain reaction (RT-PCR). Subsequently, MTT (3-(4, 5)-dimethylthiahiazo(-z-y1)-3, 5-di-phenytetrazoliumromide) assay, flow cytometry, reactive oxygen species assay kit and Western blotting were used to assay U87 cells with agonist activity of PPAR.</p><p><b>RESULTS</b>The data demonstrated that the expression of PPAR in glioma was low and negatively correlated with its pathological grade. Activation of PPAR suppresses tumor cell proliferation, delays the cell cycle at G1 phrase, and induces apoptosis and accumulation of reactive oxygen species (ROS) in U87 cells.</p><p><b>CONCLUSION</b>The expression of PPAR mRNA in human glioma was low. PPAR protein plays a critical role in the progression of glioma via the PPAR signal pathway.</p>


Subject(s)
Apoptosis , Cell Cycle Checkpoints , Cell Line, Tumor , Cell Proliferation , Gene Expression , Glioma , Genetics , Metabolism , Humans , PPAR alpha , Genetics , Metabolism , Signal Transduction
18.
Article in English | WPRIM | ID: wpr-347110

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the anti-hyperlipidemic effects of apple polyphenols extract (APE) in Triton WR-1339-induced endogenous hyperlipidemic model.</p><p><b>METHODS</b>Firstly, APE was isolated and purified from the pomace of Red Fuji Apple and contents of individual polyphenols in APE were determined using high-performance liquid chromatography-mass spectrometry (HPLC-MS). Secondly, forty male National Institude of Health (NIH) mice were randomly divided into 5 groups with 8 animals in each group. The Fenofibrate Capsules (FC) group and APE groups received oral administration of respective drugs for 7 consecutive days. All mice except those in the normal group were intravenously injected through tail vein with Triton WR-1339 on the 6th day. Serum and livers from all the mice were obtained 18 h after the injection. The changes in serum total cholesterol (TC), triglyceride (TG), lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) were measured by respective kits. Finally, expression of hepatic peroxisome proliferator-activated receptor alpha (PPARα) mRNA was measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) method. RESULTS SERUM TC AND TG LEVELS SIGNIFICANTLY INCREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY REDUCED THE SERUM LEVEL OF TG IN HYPERLIPIDEMIC MICE (P<0.01). SERUM LPL AND HTGL ACTIVITIES SIGNIFICANTLY DECREASED IN TRITON WR-1339-INDUCED MODEL GROUP COMPARED WITH THE NORMAL GROUP (P<0.05). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE SERUM ACTIVITY OF LPL IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01). FURTHERMORE, COMPARED WITH THE NORMAL GROUP, HEPATIC MRNA LEVEL OF PPARα IN THE MODEL GROUP SIGNIFICANTLY DECREASED (P<0.01). ORAL ADMINISTRATION OF APE [200 AND 400 MG/(KG DAY)] DOSE-DEPENDENTLY ELEVATED THE EXPRESSION OF PPARα IN HYPERLIPIDEMIC MICE (P<0.05 OR P<0.01):</p><p><b>CONCLUSION</b>APE could reduce TG level via up-regulation of LPL activity, which provides new evidence to elucidate the anti-hyperlipidemic effects of APE.</p>


Subject(s)
Animals , Chlorogenic Acid , Pharmacology , Therapeutic Uses , Cholesterol , Blood , Flavonoids , Pharmacology , Therapeutic Uses , Hyperlipidemias , Blood , Drug Therapy , Pathology , Hypolipidemic Agents , Pharmacology , Lipoprotein Lipase , Blood , Genetics , Male , Mice , PPAR alpha , Genetics , Metabolism , Phytotherapy , Polyethylene Glycols , RNA, Messenger , Genetics , Metabolism , Tannins , Pharmacology , Therapeutic Uses , Triglycerides , Blood , Up-Regulation
19.
Acta Pharmaceutica Sinica ; (12): 316-321, 2014.
Article in Chinese | WPRIM | ID: wpr-245083

ABSTRACT

To observe a PPAR-alpha agonist effect of N-oleoylethanolamine (OEA) on CB2 (cannabinoid receptor 2), an anti-inflammatory receptor in vascular endothelial cell, healthy HUVECs and TNF-alpha induced HUVECs were used to establish a human vascular endothelial cell inflammatory model. Different doses of OEA (10, 50 and 100 micromol x L(-1)) had been given to HUVECs, cultured at 37 degrees C for 7 h and then collected the total protein and total mRNA. CB2 protein expression was detected by Western blotting and CB2 mRNA expression was assayed by real-time PCR. As the results shown, OEA (10 and 50 micromol x L(-1)) could induce the CB2 protein and mRNA expression, but not 100 micromol x L(-1). To detect if anti-inflammation effect of OEA is partly through CB2, CB2 inhibitor AM630 was used to inhibit HUVEC CB2 expression, then the VCAM-1 expression induced by TNF-alpha was detected, or THP-1 adhere to TNF-alpha induced HUVECs was examined. OEA (50 micromol x L(-1)) could inhibit TNF-alpha induced VCAM-1 expression and THP-1 adhere to HUVECs, these effects could be partly inhibited by a CB2 inhibitor AM630. The anti-inflammation effect of OEA is induced by PPAR-alpha and CB2, suggesting that CB2 signaling could be a target for anti-atherosclerosis, OEA have wide effect in anti-inflammation, it may have better therapeutic potential in anti-inflammation in HUVECs, thus achieving anti-atherosclerosis effect.


Subject(s)
Anti-Inflammatory Agents , Pharmacology , Atherosclerosis , Pathology , Cell Adhesion , Cells, Cultured , Endocannabinoids , Pharmacology , Endothelial Cells , Cell Biology , Metabolism , Ethanolamines , Pharmacology , Humans , Indoles , Pharmacology , Monocytes , Oleic Acids , Pharmacology , PPAR alpha , RNA, Messenger , Metabolism , Receptor, Cannabinoid, CB2 , Genetics , Metabolism , Tumor Necrosis Factor-alpha , Pharmacology , Vascular Cell Adhesion Molecule-1 , Metabolism
20.
Acta Pharmaceutica Sinica ; (12): 490-496, 2014.
Article in Chinese | WPRIM | ID: wpr-245057

ABSTRACT

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.


Subject(s)
Animals , Carbolines , Chemistry , Pharmacology , Cells, Cultured , Drug Design , Hypoglycemic Agents , Chemistry , Pharmacology , Molecular Structure , PPAR alpha , PPAR gamma , Peroxisome Proliferator-Activated Receptors , Pyrimidines , Metabolism , Structure-Activity Relationship , Thiazolidinediones , Metabolism , Transfection
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