Objective To study the effect of β3 adrenergic receptor (β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPAR72) Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight...Objective To study the effect of β3 adrenergic receptor (β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPAR72) Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment (HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state (IBS) was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio (WHR), blood glucose (GLU), and insulin (INS), homeostasis model assessment insulin resistance index (HOMA-IR) of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index (BMI), WHR, percent of body fat (PBF) and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR),2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.展开更多
Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and prolif...Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。展开更多
BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activa...BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene by portal vein injection.The liver of the rats was examined histologically and hydroxyproline was assessed.In vitro primary hepatic stellate cells(HSCs)were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene.The status of HSC proliferation was measured by the MTT assay.The protein levels of PPAR-γ,α-smooth muscle actin(α-SMA)and type I collagen expression were evaluated by the Western blotting method. RESULTS:In vitro studies revealed that expression of PPAR-γ inhibited expression ofα-SMA and type I collagen in activated HSCs(P<0.01)as well as HSC proliferation(P<0.01).In vivo experiments indicated that in the early hepatic fibrosis group,the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-γtransfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group;whereas the expressions of PPAR-γ andα-SMA were different compared to the hepatic fibrosis group(P<0.01).In the sustained hepatic fibrosis group,there were significant differences in the hydroxyproline content and the expression of PPAR-γ,α-SMA,and type I collagen between each group.CONCLUSION:PPAR-γcan inhibit HSC proliferation and hepatic fibrosis,and suppressα-SMA and type I collagen expression.展开更多
Background Studies suggested that exogenous ghrelin administration could prevent early left ventricular remodeling in rats with myocardial infarction. We investigated herein whether ghrelin attenuated left ventricular...Background Studies suggested that exogenous ghrelin administration could prevent early left ventricular remodeling in rats with myocardial infarction. We investigated herein whether ghrelin attenuated left ventricular remodeling induced by hypertension and whether ghrelin's effect was mediated through the peroxisome proliferator-activated receptor gamma (PPAR-y)-dependent pathway. Methods Spontaneously hypertensive rats (8-week-old males) were randomly divided into three groups with 12 rats in each: ghrelin group (received ghrelin 100 IJg/kg subcutaneously (sc) twice daily); ghrelin+GW9662 group (received the PPAR-y antagonist GW9662 at 2 mg/kg sc, and then ghrelin as above); saline controls. Normal male Wistar Kyoto rats (n=-12) served as normal controls. Four weeks later, the effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, and histopathological examination, and gene expression analysis (PPAR-y protein and mRNA expression). The serum levels of C-reactive protein (CRP) and tumor necrosis factor (TNF)-a were detected by enzyme linked immunosorbent assay. Results Ghrelin prevented ventricular remodeling, increased PPAR-y expression in the myocardium, suppressed collagen I and collagen Ill mRNA expression, and also decreased the serum levels of TNF-a, but not CRP. All abovementioned effects of ghrelin were inhibited by GW9662. Conclusion Ghrelin inhibited ventricular remodeling induced by hypertension, and the preventive effects of ghrelin may be mediated by the anti-inflammatory actions of the PPAR-y-dependent pathway.展开更多
Mitofusin2 (Mfn2) plays a pivotal role in the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the effects of Mfn2 on the traffick- ing of intracell...Mitofusin2 (Mfn2) plays a pivotal role in the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the effects of Mfn2 on the traffick- ing of intracellular cholesterol in the foam ceils derived from rat VSMCs (rVSMCs) and also to investigate the effects of Mfn2 on the expression of adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1), adenosine triphosphate-binding cassette subfamily G member 1 (ABCG1) and peroxisome proliferator-activated receptor gamma (PPARy). The rVSMCs were co-cultured with oxi- dized low density lipoprotein (LDL, 80 ~tg/mL) to produce foam cells and cholesterol accumulation in cells. Before oxidized LDL treatment, different titers (20, 40 and 60 pfu/cell) of recombinant adenovirus containing Mfn2 gene (Adv-Mfn2) were added into the culture medium for 24 h to transfect the Mfn2 gene into the rVSMCs. Then the cells were harvested for analyses. The protein expression of Mfn2 was significantly higher in Adv-Mfn2-transfected group than in untransfected group (P〈0.05), and the ex- pression levels significantly increased when the titer of Adv-Mfn2 increased (P〈0.05). At 24 or 48 h af- ter oxidized LDL treatment, rVSMCs became irregular and their nuclei became larger, and their plasma abounded with red lipid droplets. However, the number of red lipid droplets was significantly decreased in Adv-Mfn2-transfected group as compared with untransfected group. At 48 h after oxidized LDL treatment, the intracellular cholesterol in rVSMCs was significantly increased (P〈0.05), but it was sig- nificantly decreased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05), and it also significantly decreased when the titer of Adv-Mfn2 increased (P〈0.05). The mRNA and pro- tein expression levels of ABCA1 and ABCG1 were significantly increased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05). Though the mRNA and protein expression levels of PPARy was not significantly increased (P〉0.05), the phosporylation levels of PPARy were signifi- cantly decreased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05). These results suggest that the transfection of Adv-Mfn2 can significantly reduce intracellular cholesterol in oxidized LDL-induced rVSMCs possibly by decreasing PPAR'/phosporylation and then increasing pro- tein expression levels of ABCAI and ABCG1, which may be helpful to suppress the formation of foam cells.展开更多
Background Peroxisome proliferator activated receptor γ (PPARγ) is a ligand-activated transcription factor. Activation of PPARγ has recently been demonstrated to inhibit various tumor cells growth, progression an...Background Peroxisome proliferator activated receptor γ (PPARγ) is a ligand-activated transcription factor. Activation of PPARγ has recently been demonstrated to inhibit various tumor cells growth, progression and metastasis. E-cadherin-mediated cell adhesion system is now considered to be an “invasion suppressor system” in cancer tissues. Matrix metalloproteinases-2 (MMP-2) is a prerequisite for metastasizing tumor cells. However their correlation is still unknown in gastric carcinoma. The aim of this study was to assess the expression of PPAR7, E-cadherin, MMP-2 and their correlation in gastric carcinoma and metastases. Methods Gastric carcinoma tissues and their corresponding lymph nodes with metastases and the adjacent non-tumor tissues were obtained from 54 patients with gastric cancer who underwent gastrectomy. Expression of PPARγ, E-cadherin and MMP-2 was assessed by immunohistochemical staining. Results The nuclear expression level of PPARγ in neoplastic cells was significantly lower than that in the normal controls (P〈0.001), with the expression of PPARγ being weaker in primary tumors compared with that in metastases. In all neoplastic cells, E-cadherin was expressed with abnormal patterns (cytoplasm pattern, cytoplasm and membrane pattern or absent), compared with normal cells where E-cadherin was expressed with a normal pattern (membrane pattern). Compared with the normal tissues, the expression level of E-cadherin decreased in primary tumors and further decreased in metastases (P〈0.001). Membrane staining of MMP-2 was detected in the foveolar epithelia of normal gastric mucosa, whereas predominant cytoplasm staining of MMP-2 was found in malignant tissues. The expression of MMP-2 was stronger in metastatic tissues than in primary tumors. In neoplastic foci the expression of PPARγ was negatively correlated with MMP-2 expression (P〈0.05). However, there was no correlation between E-cadherin and PPARγ or MM P-2 expression. Conclusions Down-regulation of PPARγ and E-cadherin and up-regulation of MMP-2 in neoplastic foci might be helpful to gastric carcinogenesis and metastases. An inverse relationship between PPARγ and MMP-2 in human gastric carcinoma suggests that PPARγ might modulate MMP-2 expression and affect gastric cancer metastases.展开更多
Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populatio...Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P〈0.01). Even in controls, the 482Ser(A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly(G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1α gene and MEF2C.展开更多
The aim of this investigation was to determine whether a PPAR72 Prol2Ala polymorphism was associated with insulin resistance, β-cellfunction and hypertension in Chinese populations. 289 unrelated Chinese subjects fir...The aim of this investigation was to determine whether a PPAR72 Prol2Ala polymorphism was associated with insulin resistance, β-cellfunction and hypertension in Chinese populations. 289 unrelated Chinese subjects first diagnosed Type 2 diabetes (HbAC1〈6.0) were investigated, including 132 hypertensive diabetic (HTD) subjects, 157 normotensive diabetic (NTD) subjects. Blood pressure and anthropometric measurements were collected from all participants, as well as several venous blood samples during oral glucose tolerance test (OGTT). Biochemical measurements (high-density lipoprotein (HDL) and low-density lipoprotein-cholesterol (LDL), triglycerides) and PPARγ2 Pro12Ala genotype were also determined. And insulin resistance and β-cells function was assessed by HOMA-IR and HOMA-β respectively. The frequency of subjects bearing the Pro12Ala was lower in the hypertension group (3. 03 %) than in the non-hypertension group (5.7 %) (P〈0.05) after adjusted for age, BMI and gender. Hypertensive diabetic Pro12Ala subjects had lower fasting plasma glucose level (P=0. 0127), and better glucose tolerance 60 min after oral glucose (P=0. 0361). Moreover, plasma insulin concentrations at 60 min was lower than those without A variant (P = 0. 0275), and both hypertensive Ala/Pro in HOMA-β (P : 0. 0455) and AUC for insulin (P=0. 0473) were higher, and HOMA-IR was lower (P=0. 0375) as compared with hypertensive Pro/Pro subjects. No association was observed between Prol2Ala genotype and BMI, total cholesterol, HDL- cholesterol or triglycerides in either group. Our findings suggested that the Ala 12 allele of the PPARγ2 gene may improve insulin resistance and ameliorate β-cell function reserves in T2DM with hypertension, and protect patients from hypertension in T2DM. As an important thrifty gene, environment factors may exerts an effect of PPARγ2 on glucose homeostasis and insulin resistance.展开更多
Peroxisome proliferator-activated receptor gamma (PPARy) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARy acts as an important molecule for regulating energy homeo...Peroxisome proliferator-activated receptor gamma (PPARy) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARy acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγprotein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARy signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.展开更多
Chiglitazar sodium is a new peroxisome proliferator-activated receptor(PPAR)pan-agonist with independent intellectual property rights in China.It can treat type 2 diabetes mellitus and regulate metabolism by modestly ...Chiglitazar sodium is a new peroxisome proliferator-activated receptor(PPAR)pan-agonist with independent intellectual property rights in China.It can treat type 2 diabetes mellitus and regulate metabolism by modestly activating PPARα,PPARγ,and PPARδto improve insulin sensitivity,regulate blood glucose,and promote fatty acid oxidation and utilization.Chiglitazar sodium has a significant insulin-sensitizing effect and is advantageous in reducing fasting and postprandial blood glucose levels,particularly at the 48 mg dose in patients with concomitant high triglycerides in terms of blood glucose and triglyceride level control.展开更多
目的基于分子对接技术探究天花粉活性成分与2型糖尿病(type 2 diabetes mellitus,T2DM)靶点的相互作用。方法通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,T...目的基于分子对接技术探究天花粉活性成分与2型糖尿病(type 2 diabetes mellitus,T2DM)靶点的相互作用。方法通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)和SwissTargetPrediction数据库获得天花粉活性成分及作用靶点,在GeneCards和DisGeNET数据库中获得T2DM靶点。将天花粉活性成分靶点与T2DM靶点取交集,获取药物-疾病共有靶点,导入DAVID数据库进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。构建共有靶点的蛋白质互作网络(protein-protein interaction networks,PPI),分析得出关键靶点。最后,利用Sybyl软件进行分子对接,验证活性成分与关键靶点相互作用。结果天花粉活性成分为仙人掌甾醇(schottenol)和菠菜甾醇(spinasterol),获得药物-疾病共有靶点21个。PPI、GO和KEGG富集分析表明,天花粉可能作用于过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs),进而通过PPAR信号通路和胰岛素抵抗信号通路调节糖脂代谢。分子对接表明,天花粉活性成分仙人掌甾醇和菠菜甾醇均与关键靶点过氧化物酶体增殖物激活受体γ(PPARγ)有较强的结合作用。结论天花粉活性成分仙人掌甾醇和菠菜甾醇,可能通过作用于T2DM靶点PPARγ改善胰岛素抵抗。展开更多
Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fi...Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma.An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)activity is crucial to prevent NAFLD installation.The present study aims to investigate the associations between two common PPARGC1A polymorphisms(rs8192678 and rs12640088)and the outcomes of HCV infection in a North African context.A series of 592 consecutive Moroccan subjects,including 292 patients with chronic hepatitis C(CHC),100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay.PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection(adjusted ORs=0.76 and 0.79 respectively,P[0.05,for both).Furthermore,multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression(OR=0.71;95%CI 0.20–2.49;P=0.739;OR=1.28;95%CI 0.25–6.54;P=0.512,respectively).We conclude that,in the genetic context of South Mediterranean patients,rs8192678 and rs12640088 polymorphisms of PPARGC1 A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.展开更多
基金This study was supported by the National Natural Science Foundation of China (30371223)the Major State Basic Research Development Program of China (2001CB510310).
文摘Objective To study the effect of β3 adrenergic receptor (β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPAR72) Prol2Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment (HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state (IBS) was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%, and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio (WHR), blood glucose (GLU), and insulin (INS), homeostasis model assessment insulin resistance index (HOMA-IR) of the twin pairs sharing 2 alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA4R had statistic significance. For PPAR3t2 Prol2Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index (BMI), WHR, percent of body fat (PBF) and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Condusions β3AR Trp64Arg and PPAR),2 Pro 12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci, and further studies are necessary to confirm this finding.
基金This work was supported by USA National Institutes of Health(NIH)grant,R01DK093774 to Y.K.Lee.
文摘Peroxisome proliferator-activated receptor gamma(PPARγor PPARG)is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily.It plays a master role in the differentiation and proliferation of adipose tissues.It has two major isoforms,PPARγ1 and PPARγ2,encoded from a single gene using two separate promoters and alternative splicing.Among them,PPARγ2 is most abundantly expressed in adipocytes and plays major adipogenic and lipogenic roles in the tissue.Furthermore,it has been shown that PPARγ2 is also expressed in the liver,specifically in hepatocytes,and its expression level positively correlates with fat accumulation induced by pathological conditions such as obesity and diabetes.Knockout of the hepatic Pparg gene ameliorates hepatic steatosis induced by diet or genetic manipulations.Transcriptional activation of Pparg in the liver induces the adipogenic program to store fatty acids in lipid droplets as observed in adipocytes.Understanding how the hepatic Pparg gene expression is regulated will help develop preventative and therapeutic treatments for non-alcoholic fatty liver disease(NAFLD).Due to the potential adverse effect of hepatic Pparg gene deletion on peripheral tissue functions,therapeutic interventions that target PPAR g for fatty liver diseases require fine-tuning of this gene's expression and transcriptional activity。
基金supported by a grant from the Science and Technology Commission of Shanghai Municipality(No.07JC14036)
文摘BACKGROUND:Hepatic fibrosis is a necessary step in the development of hepatic cirrhosis.In this study we used lentiviral vector-mediated transfection technology to evaluate the effect of peroxisome proliferator-activated receptor gamma(PPAR-γ) on rat hepatic fibrosis. METHODS:Hepatic fibrosis in rats was induced by CCl4 for 2 weeks(early fibrosis)and 8 weeks(sustained fibrosis).The rats were randomly divided into four groups:normal control, fibrosis,blank vector,and PPAR-γ.They were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene by portal vein injection.The liver of the rats was examined histologically and hydroxyproline was assessed.In vitro primary hepatic stellate cells(HSCs)were infected with the recombinant lentiviral expression vector carrying the rat PPAR-γgene.The status of HSC proliferation was measured by the MTT assay.The protein levels of PPAR-γ,α-smooth muscle actin(α-SMA)and type I collagen expression were evaluated by the Western blotting method. RESULTS:In vitro studies revealed that expression of PPAR-γ inhibited expression ofα-SMA and type I collagen in activated HSCs(P<0.01)as well as HSC proliferation(P<0.01).In vivo experiments indicated that in the early hepatic fibrosis group,the hydroxyproline content and the level of collagen I protein in the liver in the PPAR-γtransfected group were not significantly different compared to the hepatic fibrosis group and the blank vector group;whereas the expressions of PPAR-γ andα-SMA were different compared to the hepatic fibrosis group(P<0.01).In the sustained hepatic fibrosis group,there were significant differences in the hydroxyproline content and the expression of PPAR-γ,α-SMA,and type I collagen between each group.CONCLUSION:PPAR-γcan inhibit HSC proliferation and hepatic fibrosis,and suppressα-SMA and type I collagen expression.
文摘Background Studies suggested that exogenous ghrelin administration could prevent early left ventricular remodeling in rats with myocardial infarction. We investigated herein whether ghrelin attenuated left ventricular remodeling induced by hypertension and whether ghrelin's effect was mediated through the peroxisome proliferator-activated receptor gamma (PPAR-y)-dependent pathway. Methods Spontaneously hypertensive rats (8-week-old males) were randomly divided into three groups with 12 rats in each: ghrelin group (received ghrelin 100 IJg/kg subcutaneously (sc) twice daily); ghrelin+GW9662 group (received the PPAR-y antagonist GW9662 at 2 mg/kg sc, and then ghrelin as above); saline controls. Normal male Wistar Kyoto rats (n=-12) served as normal controls. Four weeks later, the effects of ghrelin on cardiac remodeling were evaluated by echocardiographic, hemodynamic, and histopathological examination, and gene expression analysis (PPAR-y protein and mRNA expression). The serum levels of C-reactive protein (CRP) and tumor necrosis factor (TNF)-a were detected by enzyme linked immunosorbent assay. Results Ghrelin prevented ventricular remodeling, increased PPAR-y expression in the myocardium, suppressed collagen I and collagen Ill mRNA expression, and also decreased the serum levels of TNF-a, but not CRP. All abovementioned effects of ghrelin were inhibited by GW9662. Conclusion Ghrelin inhibited ventricular remodeling induced by hypertension, and the preventive effects of ghrelin may be mediated by the anti-inflammatory actions of the PPAR-y-dependent pathway.
基金supported by the National Natural Science Foundation of China(No.30971244)
文摘Mitofusin2 (Mfn2) plays a pivotal role in the proliferation and apoptosis of vascular smooth muscle cells (VSMCs). The purpose of this study was to investigate the effects of Mfn2 on the traffick- ing of intracellular cholesterol in the foam ceils derived from rat VSMCs (rVSMCs) and also to investigate the effects of Mfn2 on the expression of adenosine triphosphate-binding cassette subfamily A member 1 (ABCA1), adenosine triphosphate-binding cassette subfamily G member 1 (ABCG1) and peroxisome proliferator-activated receptor gamma (PPARy). The rVSMCs were co-cultured with oxi- dized low density lipoprotein (LDL, 80 ~tg/mL) to produce foam cells and cholesterol accumulation in cells. Before oxidized LDL treatment, different titers (20, 40 and 60 pfu/cell) of recombinant adenovirus containing Mfn2 gene (Adv-Mfn2) were added into the culture medium for 24 h to transfect the Mfn2 gene into the rVSMCs. Then the cells were harvested for analyses. The protein expression of Mfn2 was significantly higher in Adv-Mfn2-transfected group than in untransfected group (P〈0.05), and the ex- pression levels significantly increased when the titer of Adv-Mfn2 increased (P〈0.05). At 24 or 48 h af- ter oxidized LDL treatment, rVSMCs became irregular and their nuclei became larger, and their plasma abounded with red lipid droplets. However, the number of red lipid droplets was significantly decreased in Adv-Mfn2-transfected group as compared with untransfected group. At 48 h after oxidized LDL treatment, the intracellular cholesterol in rVSMCs was significantly increased (P〈0.05), but it was sig- nificantly decreased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05), and it also significantly decreased when the titer of Adv-Mfn2 increased (P〈0.05). The mRNA and pro- tein expression levels of ABCA1 and ABCG1 were significantly increased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05). Though the mRNA and protein expression levels of PPARy was not significantly increased (P〉0.05), the phosporylation levels of PPARy were signifi- cantly decreased in Adv-Mfn2-transfected group as compared with untransfected group (P〈0.05). These results suggest that the transfection of Adv-Mfn2 can significantly reduce intracellular cholesterol in oxidized LDL-induced rVSMCs possibly by decreasing PPAR'/phosporylation and then increasing pro- tein expression levels of ABCAI and ABCG1, which may be helpful to suppress the formation of foam cells.
基金the grants from the National Natural Science Foundation of China (No. 30671904 and No. 30670949)the Doctor Subjects Foundation of the Ministry of Education of the People's Republic of China (No. 20060558010).
文摘Background Peroxisome proliferator activated receptor γ (PPARγ) is a ligand-activated transcription factor. Activation of PPARγ has recently been demonstrated to inhibit various tumor cells growth, progression and metastasis. E-cadherin-mediated cell adhesion system is now considered to be an “invasion suppressor system” in cancer tissues. Matrix metalloproteinases-2 (MMP-2) is a prerequisite for metastasizing tumor cells. However their correlation is still unknown in gastric carcinoma. The aim of this study was to assess the expression of PPAR7, E-cadherin, MMP-2 and their correlation in gastric carcinoma and metastases. Methods Gastric carcinoma tissues and their corresponding lymph nodes with metastases and the adjacent non-tumor tissues were obtained from 54 patients with gastric cancer who underwent gastrectomy. Expression of PPARγ, E-cadherin and MMP-2 was assessed by immunohistochemical staining. Results The nuclear expression level of PPARγ in neoplastic cells was significantly lower than that in the normal controls (P〈0.001), with the expression of PPARγ being weaker in primary tumors compared with that in metastases. In all neoplastic cells, E-cadherin was expressed with abnormal patterns (cytoplasm pattern, cytoplasm and membrane pattern or absent), compared with normal cells where E-cadherin was expressed with a normal pattern (membrane pattern). Compared with the normal tissues, the expression level of E-cadherin decreased in primary tumors and further decreased in metastases (P〈0.001). Membrane staining of MMP-2 was detected in the foveolar epithelia of normal gastric mucosa, whereas predominant cytoplasm staining of MMP-2 was found in malignant tissues. The expression of MMP-2 was stronger in metastatic tissues than in primary tumors. In neoplastic foci the expression of PPARγ was negatively correlated with MMP-2 expression (P〈0.05). However, there was no correlation between E-cadherin and PPARγ or MM P-2 expression. Conclusions Down-regulation of PPARγ and E-cadherin and up-regulation of MMP-2 in neoplastic foci might be helpful to gastric carcinogenesis and metastases. An inverse relationship between PPARγ and MMP-2 in human gastric carcinoma suggests that PPARγ might modulate MMP-2 expression and affect gastric cancer metastases.
文摘Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1α and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C. Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2 diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C. Results Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P〈0.01). Even in controls, the 482Ser(A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly(G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between 482Ser variant and MEF2C. Conclusions The results suggested that the 482Ser variant of PGC-1α conferred the susceptibility to type 2 diabetes in the southern Chinese population. The underlying mechanism may be attributable, at least in part, to the altered interaction between the different variants (Gly482Ser, Thr394Thr) in the PGC-1α gene and MEF2C.
文摘The aim of this investigation was to determine whether a PPAR72 Prol2Ala polymorphism was associated with insulin resistance, β-cellfunction and hypertension in Chinese populations. 289 unrelated Chinese subjects first diagnosed Type 2 diabetes (HbAC1〈6.0) were investigated, including 132 hypertensive diabetic (HTD) subjects, 157 normotensive diabetic (NTD) subjects. Blood pressure and anthropometric measurements were collected from all participants, as well as several venous blood samples during oral glucose tolerance test (OGTT). Biochemical measurements (high-density lipoprotein (HDL) and low-density lipoprotein-cholesterol (LDL), triglycerides) and PPARγ2 Pro12Ala genotype were also determined. And insulin resistance and β-cells function was assessed by HOMA-IR and HOMA-β respectively. The frequency of subjects bearing the Pro12Ala was lower in the hypertension group (3. 03 %) than in the non-hypertension group (5.7 %) (P〈0.05) after adjusted for age, BMI and gender. Hypertensive diabetic Pro12Ala subjects had lower fasting plasma glucose level (P=0. 0127), and better glucose tolerance 60 min after oral glucose (P=0. 0361). Moreover, plasma insulin concentrations at 60 min was lower than those without A variant (P = 0. 0275), and both hypertensive Ala/Pro in HOMA-β (P : 0. 0455) and AUC for insulin (P=0. 0473) were higher, and HOMA-IR was lower (P=0. 0375) as compared with hypertensive Pro/Pro subjects. No association was observed between Prol2Ala genotype and BMI, total cholesterol, HDL- cholesterol or triglycerides in either group. Our findings suggested that the Ala 12 allele of the PPARγ2 gene may improve insulin resistance and ameliorate β-cell function reserves in T2DM with hypertension, and protect patients from hypertension in T2DM. As an important thrifty gene, environment factors may exerts an effect of PPARγ2 on glucose homeostasis and insulin resistance.
文摘Peroxisome proliferator-activated receptor gamma (PPARy) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARy acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγprotein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARy signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.
文摘Chiglitazar sodium is a new peroxisome proliferator-activated receptor(PPAR)pan-agonist with independent intellectual property rights in China.It can treat type 2 diabetes mellitus and regulate metabolism by modestly activating PPARα,PPARγ,and PPARδto improve insulin sensitivity,regulate blood glucose,and promote fatty acid oxidation and utilization.Chiglitazar sodium has a significant insulin-sensitizing effect and is advantageous in reducing fasting and postprandial blood glucose levels,particularly at the 48 mg dose in patients with concomitant high triglycerides in terms of blood glucose and triglyceride level control.
文摘目的基于分子对接技术探究天花粉活性成分与2型糖尿病(type 2 diabetes mellitus,T2DM)靶点的相互作用。方法通过中药系统药理学数据库与分析平台(Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform,TCMSP)和SwissTargetPrediction数据库获得天花粉活性成分及作用靶点,在GeneCards和DisGeNET数据库中获得T2DM靶点。将天花粉活性成分靶点与T2DM靶点取交集,获取药物-疾病共有靶点,导入DAVID数据库进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto Encyclopedia of Genes and Genomes,KEGG)通路富集分析。构建共有靶点的蛋白质互作网络(protein-protein interaction networks,PPI),分析得出关键靶点。最后,利用Sybyl软件进行分子对接,验证活性成分与关键靶点相互作用。结果天花粉活性成分为仙人掌甾醇(schottenol)和菠菜甾醇(spinasterol),获得药物-疾病共有靶点21个。PPI、GO和KEGG富集分析表明,天花粉可能作用于过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs),进而通过PPAR信号通路和胰岛素抵抗信号通路调节糖脂代谢。分子对接表明,天花粉活性成分仙人掌甾醇和菠菜甾醇均与关键靶点过氧化物酶体增殖物激活受体γ(PPARγ)有较强的结合作用。结论天花粉活性成分仙人掌甾醇和菠菜甾醇,可能通过作用于T2DM靶点PPARγ改善胰岛素抵抗。
文摘Hepatitis C virus(HCV)is still one of the main causes of liver disease worldwide.Metabolic disorders,including nonalcoholic fatty liver disease(NAFLD),induced by HCV have been shown to accelerate the progression of fibrosis to cirrhosis and to increase the risk of hepatocellular carcinoma.An optimal peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PPARGC1A)activity is crucial to prevent NAFLD installation.The present study aims to investigate the associations between two common PPARGC1A polymorphisms(rs8192678 and rs12640088)and the outcomes of HCV infection in a North African context.A series of 592 consecutive Moroccan subjects,including 292 patients with chronic hepatitis C(CHC),100 resolvers and 200 healthy controls were genotyped using a TaqMan allelic discrimination assay.PPARGC1A variations at rs8192678 and rs12640088 were not associated with spontaneous clearance of HCV infection(adjusted ORs=0.76 and 0.79 respectively,P[0.05,for both).Furthermore,multivariable logistic regression analysis showed that both SNPs were not associated with fibrosis progression(OR=0.71;95%CI 0.20–2.49;P=0.739;OR=1.28;95%CI 0.25–6.54;P=0.512,respectively).We conclude that,in the genetic context of South Mediterranean patients,rs8192678 and rs12640088 polymorphisms of PPARGC1 A are neither associated with spontaneous clearance nor with disease progression in individuals infected with HCV.
基金supported by grants from The National Natural Science Foundation of China(30971268)Scientific Research Foundation for Returned Overseas Chinese Scholars from Ministry of Education[(2008)890]+1 种基金University of South China(5-XQD-2007-7)Aid Program for Science and Technology Innovative Research Team in Higher Educational Institutions of Hunan Province~~