Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:B6ZGS2 (Peroxisome proliferator activated receptor gamma)
 44 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peroxisome proliferator activated receptor gamma (PPARgamma) is the subject of intense investigation as a target for drugs against diabetes, atherosclerosis and cancer. For this reason there is considerable interest in the spectrum of compounds that bind this receptor. In this paper we have identified cis-parinaric acid (CPA) as a novel hPPARgamma ligand. The binding of this fatty acid to the receptor increases its fluorescence and causes a shift in the UV spectrum. This spectral shift is reversible by competition with other known ligands for PPARgamma. This report represents the first direct demonstration of a fatty acid binding to PPARgamma.
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PMID:cis-parinaric acid is a ligand for the human peroxisome proliferator activated receptor gamma: development of a novel spectrophotometric assay for the discovery of PPARgamma ligands. 971 68

Peroxisome proliferator activated receptor gamma (PPARgamma) plays a central role in the process of adipocyte differentiation. This receptor and its heterodimeric partner, retinoid X receptor alpha (RXRalpha), form a DNA-binding complex that regulates transcription of adipocyte-specific genes. Troglitazone, an antidiabetic drug, has recently been identified as a synthetic ligand for PPARgamma. We studied the effects of troglitazone on proliferation and differentiation of normal and malignant hematopoietic cells. Expression of PPARgamma was easily detectable by Western blot analyses in all five myeloid leukemia cell lines. Troglitazone alone (10-5 M) did not induce differentiation in any of the cell lines; however, this compound suppressed the clonal growth (10-75% of inhibition) of all five myeloid leukemia cell lines. Myelomonocytic U937 cells, which were the most responsive to the growth suppressing effects of troglitazone, were arrested in the G1 phase of the cell cycle when cultured with this compound. Simultaneous treatment of myeloid leukemia cell lines with both troglitazone and a ligand that specifically binds either RXR (LG100268), or retinoic acid receptors (RAR, ATRA, ALART1550), or both (9-cis RA) resulted in additive suppression of clonal growth. In summary, our studies showed that troglitazone when combined with a retinoid was a moderately potent inhibitor of clonogenic growth of acute myeloid leukemia cells.
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PMID:Growth inhibition of myeloid leukemia cells by troglitazone, a ligand for peroxisome proliferator activated receptor gamma, and retinoids. 1053 88

Peroxisome proliferator activated receptor gamma (PPARgamma) is a nuclear hormone receptor that has been shown to regulate differentiation and cell growth. Studies of the differentiative effects of PPARgamma agonists on several cancer cell lines led to the hypothesis that dysfunction of PPARgamma contributes to tumorigenesis. These functional observations were strengthened by genetic evidence: somatic loss-of-function mutations in PPARG, encoding PPARgamma, in sporadic colorectal carcinomas and somatic translocation of PAX8 and PPARG in follicular thyroid carcinoma. Recently overrepresentation of the H449H variant was found in a cohort of American patients with glioblastoma multiforme. The glioblastoma multiforme data suggest that PPARG contributes common, low-penetrance alleles for cancer susceptibility. To test this hypothesis in a broader range of cancers we examined a series of carcinomas of the cervix, endometrium, ovary, prostate, and kidney for germline sequence variation in PPARG. In addition to the two common sequence variants, P12A and H449H, there were five other sequence variants. P12A alleles were underrepresented in renal cell carcinoma patients compared to country-of-origin race-matched controls (3.75% vs. 12.1%, P<0.04). In contrast, the H449H variant was overrepresented in individuals with endometrial carcinoma compared to controls (14.4% vs. 6.25%, P<0.02). These observations lend genetic evidence consistent with our hypothesis that PPARG serves as a common, low-penetrance susceptibility gene for cancers of several types, especially those epidemiologically associated with obesity and fat intake.
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PMID:Opposite association of two PPARG variants with cancer: overrepresentation of H449H in endometrial carcinoma cases and underrepresentation of P12A in renal cell carcinoma cases. 1151 19

Peroxisome proliferator activated receptor gamma (PPARgamma) is a member of the nuclear receptor superfamily. Ligand activation of PPARgamma has been shown to cause growth arrest in several human tumor cell types, but the underlying molecular mechanism has not been elucidated. We report here that the PPARgamma ligand troglitazone (TRO) inhibited MCF-7 cell proliferation by blocking events critical for G1 --> S progression. Flow cytometry demonstrated that TRO at 20 microM increased the percentage of cells in G1 from 51 to 69% after 24 h. Accumulation of cells in G1 was accompanied by an attenuation of Rb protein phosphorylation associated with decreased CDK4 and CDK2 activities. Inhibition of CDK activity by TRO correlates with decreased protein levels for several G1 regulators of Rb phosphorylation (cyclin D1, and CDKs 2, 4, and 6). Overexpression of cyclin D1 partially rescued MCF-7 cells from TRO-mediated G1 arrest. Targeting of G1 regulatory proteins, particularly cyclin D1, and the resulting induction of G1 arrest by TRO may provide a novel antiproliferative therapy for human breast cancer.
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PMID:Troglitazone inhibits growth of MCF-7 breast carcinoma cells by targeting G1 cell cycle regulators. 1152 86

1. Peroxisome proliferator activated receptor gamma (PPARgamma) has been implicated in several cellular pathways assumed to beneficially affect heart failure progression. In contrast, population-based studies demonstrate an increased incidence of heart failure in patients treated with PPARgamma agonists. Therefore, we examined the effect of pioglitazone, a PPARgamma agonist, on chronic left ventricular remodeling after experimental myocardial infarction (MI) in mice. 2. Mice were treated with placebo or pioglitazone (20 mg x kg(-1) by gavage) from week 1 to week 6 after ligation of the left anterior descending artery. Serial transthoracic echocardiography was performed at weeks 1, 3, and 6. 3. Over 6 weeks, there was no difference in mortality (placebo 12%, pioglitazone 10%). Echocardiography showed significant left ventricular dilatation in animals with MI (week 6, end-systolic area, placebo sham 9.6+/-1.3 vs placebo MI 14.4+/-2.5 mm(2)). However, there was no difference between the placebo and pioglitazone groups (week 6, end-systolic area, pioglitazone MI 14.8+/-2.9 mm(2), P=NS vs placebo). 4. Moreover, there were no changes in metabolic parameters, inflammation, and collagen deposition. Endothelial function in the aorta was not changed by PPARgamma activation. 5. In conclusion, PPARgamma activation did not adversely affect left ventricular remodeling and survival in mice with chronic MI. However, we were also not able to identify a protective effect of pioglitazone.
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PMID:Peroxisome proliferator activated-receptor agonism and left ventricular remodeling in mice with chronic myocardial infarction. 1466 33

Peroxisome proliferator activated receptors are nuclear hormone receptors that regulate the expression of genes containing a peroxisome proliferator activated receptor response element. We report here that the human bcl-2 gene contains a functional peroxisome proliferator activated receptor response element in the 3' untranslated region. Peroxisome proliferator activated receptor gamma bound the human bcl-2 peroxisome proliferator activated receptor response element in gel shift assays and co-transfection of this receptor led to increased luciferase activity from a reporter plasmid containing the human bcl-2 peroxisome proliferator activated receptor response element. Examination of peroxisome proliferator activated receptor gamma-transfected cells demonstrated an increased amount of bcl-2 message compared to empty vector-transfected cells. Confocal analyses confirmed that more Bcl-2 protein was present in peroxisome proliferator activated receptor gamma-transfected cells compared to control-transfected cells. The functionality of the increased Bcl-2 protein was examined using resistance to bile salt-induced apoptosis as the endpoint. Peroxisome proliferator activated receptor gamma-transfected cells were almost twice as resistant as control-transfected cells. These data show that PPARgamma can mediate transcription of bcl-2, resulting in an increase in Bcl-2 protein and protection from apoptosis. We discuss these findings with regards to their potential implications for colon carcinogenesis.
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PMID:Identification of a functional peroxisome proliferator activated receptor response element in the 3' untranslated region of the human bcl-2 gene. 1506 55

Peroxisome proliferator activated receptor gamma (PPARgamma) agonist has not only antidiabetic effect but also a protective effect against various types of injury of the kidney. The protective effects of PPARgamma agonists are observed in diabetic nephropathy and non-diabetic renal diseases such as 5/6 ablation model of renal failure, experimental glomerulonephritis, ischemia-reperfusion injury, hypertensive nephropathy and cyclosporin-induced renal injury. The mechanism of renoprotection by PPARgamma agonist is multifactorial. Anti-fibrotic and anti-inflammatory effects, suppression of renin-angiotensin system, vascular protective effect and antiapoptotic effect were proposed.
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PMID:Protective effect of peroxisome proliferator activated receptor gamma agonists on diabetic and non-diabetic renal diseases. 1617 87

The recent observations that Peroxisome proliferator activated receptor gamma coactivator 1 alpha (PGC1A) is responsible for the induction of reactive oxygen species (ROS) detoxifying agents and that ROS triggers insulin resistance, support the role that this gene could play in the onset of Type 2 diabetes mellitus (T2DM). Two PGC1A variants Thr394Thr (rs2970847) and Gly482Ser (rs8192673) were genotyped in 822 subjects (351 T2DM cases and 471 controls) from two North Indian populations, represented as Group 1 (Kashmir population) and Group 2 (Punjab and Jammu population). Both Groups 1 and 2 showed a significant association of Thr394Thr variant with T2DM after applying Bonferroni corrections (P=0.001 and 0.012, respectively). Logistic regression analysis for Thr394Thr susceptible genotypes together (rs2970847 G/A and A/A) conferred a 1.89-(95%CI 1.25-2.85) fold higher risk for T2DM in Group 1 and 1.81-(95%CI 1.19-2.78) fold risk in Group 2. The susceptible, Ser482 (rs8192673 G/A and A/A) genotypes, gave a 2.04 (95%CI 1.47-3.03) fold higher risk for T2DM in Group 1. Mitochondrial genotype backgrounds observed in association with T2DM (Bhat et al. 2007), when studied in combination with PGC1A variants, showed an increased prevalence in controls with mt10398G and 16189T along with G/G genotype background at the two polymorphic loci of PGC1A. These observations suggest that the two genotype backgrounds together could provide protection against T2DM.
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PMID:PGC-1alpha Thr394Thr and Gly482Ser variants are significantly associated with T2DM in two North Indian populations: a replicate case-control study. 1739 Jan 50

Peroxisome proliferator activated receptor gamma 2 (PPARg2) is the nutritionally regulated isoform of PPARg. Ablation of PPARg2 in the ob/ob background, PPARg2(-/-) Lep(ob)/Lep(ob) (POKO mouse), resulted in decreased fat mass, severe insulin resistance, beta-cell failure, and dyslipidaemia. Our results indicate that the PPARg2 isoform plays an important role, mediating adipose tissue expansion in response to positive energy balance. Lipidomic analyses suggest that PPARg2 plays an important antilipotoxic role when induced ectopically in liver and muscle by facilitating deposition of fat as relatively harmless triacylglycerol species and thus preventing accumulation of reactive lipid species. Our data also indicate that PPARg2 may be required for the beta-cell hypertrophic adaptive response to insulin resistance. In summary, the PPARg2 isoform prevents lipotoxicity by (a) promoting adipose tissue expansion, (b) increasing the lipid-buffering capacity of peripheral organs, and (c) facilitating the adaptive proliferative response of beta-cells to insulin resistance.
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PMID:PPAR gamma 2 prevents lipotoxicity by controlling adipose tissue expandability and peripheral lipid metabolism. 1746 82

Adiponectin is a protein hormone involved in maintaining energy homeostasis in metabolically active tissues. It enhances glucose and lipid metabolism via activation of AMP-dependent kinase (AMPK) in skeletal muscle and liver. Energy homeostasis is vital for the heart to work as a pump. In this study, we investigated whether adiponectin and its receptors are expressed in adult ventricular cardiomyocytes. We observed adiponectin transcript and protein in cultured ventricular cardiomyocytes isolated from adult rat, by quantitative real-time PCR, ELISA assays, Western blots, and immunofluorescent staining. In addition, we detected adiponectin receptor (AdipoR1 and AdipoR2) expression in the heart. AdipoR1 was expressed in rat myocardium at a level of approximately 50% of that in skeletal muscle; whereas adipoR2 was expressed at a similar level to that in liver. Rosiglitazone, a Peroxisome proliferator activated receptor gamma (PPARgamma) activator, substantially elevated expression of adiponectin in cultured cardiomyocytes and its secretion into cultured media. Rosiglitazone also increased adipoR1 and adipoR2 expression in cardiomyocytes. Treatment of recombinant globular adiponectin in cultured cardiomyocytes increased fatty acid oxidation and glucose uptake via activation of AMPK, suggesting a role for adiponectin in cardiac energy metabolism. Together, these data establish the existence of a local cardiac-specific adiponectin system that is regulated by PPARgamma. Moreover, these findings indicate a role for adiponectin on normal myocardial energy homeostasis, in part, through the activation of AMPK.
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PMID:Adiponectin and its receptors are expressed in adult ventricular cardiomyocytes and upregulated by activation of peroxisome proliferator-activated receptor gamma. 1753 4


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