TY - JOUR. T1 - Transcriptional regulation of nephrin gene by peroxisome proliferator-activated receptor-γ agonist. T2 - Molecular mechanism of the antiproteinuric effect of pioglitazone. AU - Benigni, Ariela. AU - Zoja, Carla. AU - Tomasoni, Susanna. AU - Campana, Marco. AU - Corna, Daniela. AU - Zanchi, Cristina. AU - Gagliardini, Elena. AU - Garofano, Elvira. AU - Rottoli, Daniela. AU - Ito, Takahito. AU - Remuzzi, Giuseppe. PY - 2006/6. Y1 - 2006/6. N2 - The renoprotective potential of the peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone was explored in an immune model of progressive nephropathy, passive Heymann nephritis (PHN), compared with that of an angiotensin II receptor antagonist, taken as standard therapy for renoprotection. PHN rats received orally vehicle, pioglitazone (10 mg/kg twice daily), or candesartan (1 mg/kg twice daily) from months 2 to 8. Pioglitazone reduced proteinuria as effectively as candesartan and limited renal functional and ...
The IUPHAR/BPS Guide to Pharmacology. Peroxisome proliferator-activated receptor-α - 1C. Peroxisome proliferator-activated receptors. Detailed annotation on the structure, function, physiology, pharmacology and clinical relevance of drug targets.
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment ...
The mechanisms of the improvement of glucose homeostasis through angiotensin receptor blockers are not fully elucidated in hypertensive patients. We investigated the effects of telmisartan on insulin signaling and glucose uptake in cultured myotubes and skeletal muscle from wild-type and muscle-specific peroxisome proliferator-activated receptor (PPAR) δ knockout (MCK-PPARδ−/−) mice. Telmisartan increased PPARδ expression and activated PPARδ transcriptional activity in cultured C2C12 myotubes. In palmitate-induced insulin-resistant C2C12 myotubes, telmisartan enhanced insulin-stimulated Akt and Akt substrate of 160 kDa (AS160) phosphorylation as well as Glut4 translocation to the plasma membrane. These effects were inhibited by antagonizing PPARδ or phosphatidylinositol-3 kinase, but not by PPARγ and PPARα inhibition. Palmitate reducing the insulin-stimulated glucose uptake in C2C12 myotubes could be restored by telmisartan. In vivo experiments showed that telmisartan treatment ...
AIM To investigate the role of hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS (6 mg/kg, i.p.). RESULTS PPAR-γ activity in rats undergoing BDL was significantly lower than in the sham-controls. Hepatic
Ligands for peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) increase skeletal muscle fatty acid catabolism, improve insulin sensitivity, increase serum high-density lipoprotein cholesterol, elicit anti-inflammatory activity and induce terminal differentiation. Contradictory findings are also reported suggesting that PPARβ/δ ligands potentiate tumorigenesis by increasing cell proliferation, by inhibiting apoptosis through phosphorylation of Akt and by increasing cyclooxygenase-2 (COX2) and vascular endothelial growth factor (VEGF) expression. The contradictory findings could be due to differences in the model system (cancer cell line versus in vivo), differences in cell culture conditions (with and without serum) or differences in ligands. The present study examined the effect of two different PPARβ/δ ligands (GW0742 and GW501516) in human cancer cell lines (HT29, HCT116, LS-174T, HepG2 and HuH7) cultured in the presence or absence of serum and compared in vitro analysis with in ...
Breast cancer in women in the United States accounts for more deaths than any other malignancy (1) . The majority of these breast tumors originate from the ductile epithelia, and infiltrating ductal carcinomas account for ,70% of all of the breast cancers (2) . Current chemotherapies are accompanied by significant toxicity and benefit only a limited number of patients. The limited number of therapeutic options and the high degree of prevalence have stimulated the search for new and more selective molecular targets for the management of breast cancer. Cancer is the result of dysregulation of differentiation and apoptosis. The peroxisome proliferator-activated receptor-γ (PPARγ) as an important mediator of terminal differentiation in adipocytes (3 , 4) has led to the examination of its role in mediating similar programs in breast adenocarcinomas (5, 6, 7) .. PPARγ is a member of the nuclear hormone receptor superfamily and plays critical roles in adipogenesis (3 , 4 , 8) , insulin-mediated ...
Peritoneal dialysis patients are at increased risk of cardiovascular morbidity and mortality and are related to the presence of accelerated atherosclerosis. Other than the traditional cardiovascular risk factors, there is increasing evidence that inflammation is associated with the development of atherosclerosis and cardiovascular events in both the general and dialysis population. C-reactive protein is predictive of higher all-cause mortality and cardiovascular mortality, independent of other cardiovascular risk factors and atherosclerotic vascular disease. As a considerable proportion of peritoneal dialysis patients showed elevated C-reactive protein, it raises an important question as to whether lowering C-reactive protein will have any cardiovascular and survival benefit in these patients. On the other hand, insulin resistance with associated hyperinsulinemia is frequently observed in chronic renal failure and dialysis patients. Although the exact mechanism of insulin resistance needs ...
PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research focusing on mechanisms involved in the activation of peroxisome proliferator-activated receptors (PPARs), as well as their role in the regulation of cellular differentiation, development, energy homeostasis and metabolic function. The journal also welcomes preclinical and clinical trials of drugs that can modulate PPAR activity, with a view to treating chronic diseases and disorders such as dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, and obesity.
Peroxisome proliferator-activated receptor-gamma (PPAR?) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPAR?, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPAR? agonists from the ZINC library, and 10,000 of these were selected for docking with PPAR? based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values ...
Purpose.: Vascular endothelial growth factor (VEGF)-induced retinal vascular permeability contributes to diabetic macular edema (DME), a serious vision-threatening condition. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) antagonist/reverse agonist, GSK0660, inhibits VEGF-induced human retinal microvascular endothelial cell (HRMEC) proliferation, tubulogenesis, and oxygen-induced retinal vasculopathy in newborn rats. These VEGF-induced HRMEC behaviors and VEGF-induced disruption of endothelial cell junctional complexes may well share molecular signaling events. Thus, we sought to examine the role of PPARβ/δ in VEGF-induced retinal hyperpermeability. Methods.: Transendothelial electrical resistance (TEER) measurements were performed on HRMEC monolayers to assess permeability. Claudin-1/Claudin-5 localization in HRMEC monolayers was determined by immunocytochemistry. Extracellular signal-regulated protein kinases 1 and 2 (Erk 1/2) phosphorylation, VEGF receptor 1 (VEGFR1) and R2 ...
Peroxisome proliferator-activated receptor-gamma (PPAR) is a nuclear transcription factor that regulates many genes and is involved in comprehensive natural functions. appearance claim that PPAR immunoassays may possibly not be suitable when used in combination with fresh homogenates of adipose and spleen tissues. Validation of the assay with each individual cells is recommended. Keywords: Immunoassay, peroxisome proliferator-activated receptor-gamma, rosiglitazone Intro Peroxisome proliferator-activated receptor-gamma (PPAR) is definitely a nuclear transcription element that regulates the manifestation of many genes. PPAR is definitely involved in large varieties of biological functions, including lipid and glucose metabolisms, anti-inflammatory effects, and has considerable cardiovascular effects.[1C5] Synthetic activators of PPAR, the thiazolidinediones (TZD), have been utilized for treatment of type II diabetes since the 1990s.[6] Dedication of PPAR activity and expression in various ...
Here, we investigated the mechanisms by which PPARδ agonists control expression of 14-3-3ε, a key antiinflammatory protein in endothelial cells.12 Our data not only provide evidence that PPARδ modulates expression of YWHAE gene and 14-3-3ε protein under resting conditions but also demonstrate that this nuclear receptor upregulates 14-3-3ε expression by targeting transcription via a PPRE-independent pathway involving colocalization of C/EBPβ and PPARδ on YWHAE promoter. Several lines of evidence support these conclusions. First, PPARδ agonists regulated YWHAE promoter activity in a concentration- and time-dependent manner. Concordantly, YWHAE promoter was upregulated by PPARδ overexpression, whereas specific PPARγ and PPARα ligands had no effect on YWHAE promoter under our experimental conditions. Second, PPARδ activation increased 14-3-3ε mRNA and protein expression in both primary and spontaneously transformed endothelial cell lines, whereas PPARδ knockdown depressed basal and ...
We investigated whether ancestral liver damage leads to heritable reprogramming of hepatic wound healing in male rats. We found that a history of liver damage corresponds with transmission of an epigenetic suppressive adaptation of the fibrogenic component of wound healing to the male F-1 and F-2 generations. Underlying this adaptation was less generation of liver myofibroblasts, higher hepatic expression of the antifibrogenic factor peroxisome proliferator-activated receptor gamma (PPAR-gamma) and lower expression of the profibrogenic factor transforming growth factor beta 1 (TGF-beta 1) compared to rats without this adaptation. Remodeling of DNA methylation and histone acetylation underpinned these alterations in gene expression. Sperm from rats with liver fibrosis were enriched for the histone variant H2A.Z and trimethylation of histone H3 at Lys27 (H3K27me3) at PPAR-gamma chromatin. These modifications to the sperm chromatin were transmittable by adaptive serum transfer from fibrotic rats to ...
Nitro-fatty acids (NO(2)-FA) are electrophilic signaling mediators formed by reactions of nitric oxide and nitrite. NO(2)-FA exert anti-inflammatory signaling actions through post-translational protein modifications. We report that nitro-oleic acid (OA-NO(2)) stimulates proMMP-7 and proMMP-9 proteolytic activity via adduction of the conserved cysteine switch domain thiolate. Biotin-labeled OA-NO(2) showed this adduction occurs preferentially with latent forms of MMP, confirming a role for thiol alkylation by OA-NO(2) in MMP activation. In addition to regulating pro-MMP activation, MMP expression was modulated by OA-NO(2) via activation of peroxisome proliferator-activated receptor-γ. MMP-9 transcription was decreased in phorbol 12-myristate 13-acetate-stimulated THP-1 macrophages to an extent similar to that induced by the peroxisome proliferator-activated receptor-γ agonist Rosiglitazone. This was affirmed using a murine model of atherosclerosis, ApoE(-/-) mice, where in vivo OA-NO(2) administration
In the present study, we examined PPARγ regulation by Ang II in mouse aortic VSMCs. The findings of this study demonstrate that Ang II decreases expression of PPARγ via AT1 receptors in VSMCs. Furthermore, this Ang II-induced decrease in PPARγ occurs via TGF-β1 and the p38 MAPK pathway. Ang II activated p38 via TGF-β1 and decreased PPARγ through HDAC3 without involving Smad signaling.. In this study, blockade of AT1 receptors with losartan inhibited Ang II-induced PPARγ reduction. AT1 receptors mediate most responses to Ang II, and this receptor subtype is predominantly expressed in VSMCs.25,26 AT1 receptor antagonists have been shown to activate PPARγ in various cell types, including adipocytes and VSMCs.27,28 Among the various AT1 receptor antagonists, telmisartan has been shown to activate PPARγ within a 10 μmol/L concentration,28 whereas the losartan activates PPARγ only at a high concentration (100 μmol/L).29 In our study, losartan at 10 μmol/L inhibited Ang II-induced PPARγ ...
Peroxisome proliferator-activated receptor gamma (PPAR-γ or PPARG), also known as the glitazone receptor, or NR1C3 (nuclear receptor subfamily 1, group C, member 3) is a type II nuclear receptor that in humans is encoded by the PPARG gene. PPARG is mainly present in adipose tissue, colon and macrophages. Two isoforms of PPARG are detected in the human and in the mouse: PPAR-γ1 (found in nearly all tissues except muscle) and PPAR-γ2 (mostly found in adipose tissue and the intestine). PPARG regulates fatty acid storage and glucose metabolism. The genes activated by PPARG stimulate lipid uptake and adipogenesis by fat cells. PPARG knockout mice fail to generate adipose tissue when fed a high-fat diet. This gene encodes a member of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors. PPARs form heterodimers with retinoid X receptors (RXRs) and these heterodimers regulate transcription of various genes. Four subtypes of PPARs are known: PPAR-alpha, PPAR-delta, ...
The present study demonstrates that both PPAR-α and PPAR-γ are expressed in various rat tissues, including blood vessels, heart, muscle, kidney, liver, and adipose tissue. There is a differential expression of PPAR-α and PPAR-γ during development in SHR, a genetic model of hypertension, compared with control WKY rats. We demonstrate for the first time that in aorta from young, prehypertensive SHR, PPAR-α and PPAR-γ levels are similar, whereas in mesenteric arteries from young SHR, PPAR-α and PPAR-γ levels were greater than in age-matched WKY. In established hypertension in adult SHR, however, PPAR-α and PPAR-γ levels in aorta and mesenteric arteries were greater than in age-matched WKY. Cell culture confirmed the expression of PPARs, particularly PPAR-γ, in VSMCs.. Expression of PPARs was primarily thought to be limited to tissues such as liver and fat, in which they participate in the regulation of lipid metabolism.18 Recently, it was suggested that PPAR activators not only regulate ...
Cardiac hypertrophy is characterized by increased protein synthesis44 and size of existing cardiomyocytes,45 leading to increased cardiac muscle mass.46 Agonists of nuclear receptor PPAR-γ have been shown to inhibit both protein synthesis and cardiac hypertrophy induced by pressure overload.10,11 To elucidate the physiological function of PPAR-γ in cardiomyocytes, we used Cre-loxP system to genetically inactivate this gene specifically in cardiomyocytes of CM-PGKO mice.. CM-PGKO mice displayed age-progressive cardiac hypertrophy, indicating that PPAR-γ normally suppresses cardiomyocyte growth. Despite this hypertrophy, the resting cardiac systolic function in CM-PGKO mice was comparable to littermate control mice at the age of 6 months. In fact, at this time point, there may be a subtle improvement in systolic function over baseline, which may lead to the lower resting HR that was noted. Whether function will be maintained as these mice continue to age will need to be further evaluated. What ...
In this study, we demonstrated that activation of PPAR-α interrupted the earliest ET-1-induced events, ie, JNK activation, c-Jun phosphorylation, and c-Jun induction in cardiomyocytes. Because JNKs regulate the AP-1 DNA binding activity through phosphorylation of the 2 serine residues in the NH2-terminal region of c-Jun, 1 of the AP-1 components,19 fenofibrate, would inhibit AP-1 activity partly via JNK pathway inhibition. Activation of ERK has been implicated in features of the hypertrophic response in an in vitro model.10 Also in our study, ERKs were markedly activated by ET-1 in cardiomyocytes, but this was not affected by fenofibrate. Therefore, the inhibitory effect of fenofibrate on ET-1-related hypertrophic responses might be mediated through interfering with the JNK pathway rather than the ERK pathway.. We demonstrated that fenofibrate inhibited ET-1 promoter activity, preproET-1 mRNA expression, and hypertrophy in ET-1-stimulated cardiomyocytes. To gain additional insight into the ...
Impairment of the BBB is a critical event in the development and progression of several diseases that affect the CNS. We demonstrated here that increased BBB permeability with downregulation of TJ and AJ proteins was involved in T2DM-induced cognitive impairment. TJs present between cerebral endothelial cells perform diffusion barrier functions of the BBB and consist of many proteins, such as claudin 3, claudin 5, occludin, and ZO-1. On the other hand, AJs are required for the correct organization of TJs and are largely composed of VE-cadherin in endothelial cells.1 Therefore, alteration of the interaction between these TJ proteins and VE-cadherin plays an essential role in modulating BBB function. Our results are consistent with these ideas and previous observations, suggesting that reduced ZO-1 and occludin expression, for example, might contribute to enhanced BBB permeability in diabetes mellitus.10 However, further alterations of BBB ultrastructure in diabetic patients or animal models are a ...
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Genetic heterogeneity, lifestyle factors, gene-gene or gene-environment interactions are the determinants of T2D which puts Hispanics and populations with African ancestry at higher risk of developing T2D. In this dissertation, the genetic associations of PPARGC1A polymorphisms with T2D and its related phenotypes (metabolic markers) in Haitian Americans (cases=110, controls=116), African Americans (cases=120, controls=124) and Cuban Americans (cases=160, controls=181) of South Florida were explored. Five single nucleotide polymorphisms of gene PPARGC1A were evaluated in each ethnicity for their disease association. In Haitian Americans, rs7656250 (OR= 0.22, pp=0.03) had significant protective association with T2D but had risk association in African Americans for rs7656250 (OR=1.02, p=0.96) and rs4235308 (OR=2.53, p=0.03). We found that in Haitian American females, both rs7656250 (OR=0.23, pp=0.03) had protective association with T2D. In African American females, rs7656250 (OR=1.14, p=0.78) had risk
To examine the complex and multifactorial processes in early AVS in vivo, we combined a broad genomics-based approach with precise spatial resolution in a large animal model. To our knowledge, the present study is the first to examine the valve endothelium in the earliest stages of AVS and to identify a spatial shift of phenotype balance in response to a brief systemic insult. We found that the aortic side endothelium is much more responsive to HC than the adjacent ventricular side endothelium, and unexpectedly expressed overall protective pathways on the side vulnerable to AVS.. Differential endothelial responses to HC were identified using four different genomewide comparisons: two within-animal comparisons, in which the aortic and ventricular sides were compared; and two between-animal comparisons, in which the effect of HC on a single side of the valve was considered. These single-side analyses between NC and HC swine provided insight about the within-animal comparisons. For example, the ...
The metabolic nuclear receptors act as metabolic and toxicological sensors, enabling the organism to quickly adapt to environmental changes by inducing the appropriate metabolic genes and pathways. Ligands for these metabolic receptors are compounds from dietary origin, intermediates in metabolic pathways, drugs, or other environmental factors that, unlike classical nuclear receptor ligands, are present in high concentrations. Metabolic receptors are master regulators integrating the homeostatic control of (a) energy and glucose metabolism through peroxisome proliferator-activated receptor gamma (PPARgamma); (b) fatty acid, triglyceride, and lipoprotein metabolism via PPARalpha, beta/delta, and gamma; (c) reverse cholesterol transport and cholesterol absorption through the liver X receptors (LXRs) and liver receptor homolog-1 (LRH-1); (d) bile acid metabolism through the farnesol X receptor (FXR), LXRs, LRH-1; and (e) the defense against xeno- and endobiotics by the pregnane X receptor/steroid ...
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Results MiR-155 expression was significantly increased in the development of DAH. Disease progression was reduced in miR-155-/- mice and by in vivo silencing of miR-155 using miR-155 antagomir. MiR-155 silencing dampened pristane-induced ectopic activation of multiple inflammatory pathways, and reduced the expression of pro-inflammatory cytokines. Several negative regulators of nuclear factor (NF)-κB signalling were inhibited by pristane, and were re-activated in miR-155-/- mice. In particular, the anti-inflammatory factor peroxisome proliferator-activated receptor-α was identified as a direct target of miR-155. ...
The peroxisome proliferator-activated receptor gamma (PPARG), Pro12Ala and the insulin receptor substrate (IRS1), Gly972Arg confer opposite effects on insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the independent and joint effects of PPARG Pro12Ala and IRS1 Gly972Arg on markers of insulin resistance and T2DM in an African population with elevated risk of T2DM. In all 787 (176 men) mixed-ancestry adults from the Bellville-South community in Cape Town were genotyped for PPARG Pro12Ala and IRS1 Gly972Arg by two independent laboratories. Glucose tolerance status and insulin resistance/sensitivity were assessed. Genotype frequencies were 10.4% (PPARG Pro12Ala) and 7.7% (IRS1 Gly972Arg). Alone, none of the polymorphisms predicted prevalent T2DM, but in regression models containing both alleles and their interaction term, PPARG Pro12 conferred a 64% higher risk of T2DM. Furthermore PPARG Pro12 was positively associated in adjusted linear regressions with increased 2-hour post-load
The aim of the present study was to examine the role of endogenous peroxisome proliferator-activated receptor-α (PPAR-α) ligand on the permeability and structure of small intestine tight junctions (TJs) in an animal model of experimental colitis, induced by dinitrobenzene sulfuric acid (DNBS). Four days after colitis induction with DNBS, the ileal TJs were studied by means of transmission electron microscopy using lanthanum nitrate and immunohistochemistry of occludin, zonula occludens 1, and claudin 2. Administration of DNBS to wild-type mice induced colon injury associated with a significant increase of plasma and colon tumor necrosis factor-α levels and with a significant increase of ileal permeability. Distal colitis in mice induced an increase of TJ permeability throughout the entire small intestine, and the extent of alterations correlates with colonic damage. Small intestinal permeability was associated with the presence of apoptosis (evaluated by FAS ligand expression and terminal ...
TY - JOUR. T1 - Peroxisome proliferator-activated receptor γ and its role in adipocyte homeostasis and thiazolidinedione-mediated insulin sensitization. AU - Wang, Qiong A.. AU - Zhang, Fang. AU - Jiang, Lei. AU - Ye, Risheng. AU - An, Yu. AU - Shao, Mengle. AU - Tao, Caroline. AU - Gupta, Rana K. AU - Scherer, Philipp E. PY - 2018/5/1. Y1 - 2018/5/1. N2 - Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo. Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are ...
Nuclear receptor that binds peroxisome proliferators such as hypolipidemic drugs and fatty acids. Once activated by a ligand, the nuclear receptor binds to DNA specific PPAR response elements (PPRE) and modulates the transcription of its target genes, such as acyl-CoA oxidase. It therefore controls the peroxisomal beta-oxidation pathway of fatty acids. Key regulator of adipocyte differentiation and glucose homeostasis. ARF6 acts as a key regulator of the tissue-specific adipocyte P2 (aP2) enhancer. Acts as a critical regulator of gut homeostasis by suppressing NF-kappa-B-mediated proinflammatory responses. Plays a role in the regulation of cardiovascular circadian rhythms by regulating the transcription of ARNTL/BMAL1 in the blood vessels (PubMed:19041764).
NCOR2, also known as SMRT, is a transcriptional corepressor that maintains the transcriptional silencing of certain target genes. NCOR2 expression and its occupancy on peroxisome proliferator-activated receptor (PPAR) target gene promoters are increased with age in major metabolic tissues. Shifting its repressive activity towards PPARs, by selectively disabling one of its two major receptor-interacting domains, resulted in premature ageing in mice and related metabolic diseases accompanied by reduced mitochondrial function and antioxidant gene expression. Additionally, in a preliminary analysis, several human polymorphisms were found to be associated with type 2 diabetes [2196]. ...
Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a member of the nuclear hormone receptor superfamily. It is expressed in adipocytes, immune cells, and cardiovascular cells that include cardiomyocytes, endothelial cells, and smooth mus
The angiotensin II type 1 receptor blocker (ARB) telmisartan was reported to activate the peroxisome proliferator-activated receptor-γ (PPARγ) in transactivation assays, whereas other ARBs, with the possible exception of irbesartan, did not (1). Telmisartan also induced adipogenesis and increased the expression of PPARγ target genes in preadipocyte fibroblasts (1), both of which are hallmark properties of PPARγ agonists.. We report a case of a 52-year-old man with hypertension, visceral obesity (BMI 34.4 kg/m2), and impaired glucose tolerance (pre-diabetes), in whom administration of telmisartan (80 mg/day) normalized blood pressure, improved insulin resistance, and reduced plasma triglycerides. During the 10 weeks after initiating telmisartan, … ...
We document here for the first time that endogenous ligands of PPARgamma may contribute to the protection against renal I/R injury afforded by LPS pretreatment in the rat.
Carbon monoxide (CO) dampens pro-inflammatory responses in a peroxisome proliferator-activated receptor-γ (PPARγ) and p38 mitogen-activated protein kinase (MAPK) dependent manner. Previously, we demonstrated that CO inhibits lipopolysaccharide (LPS
A Diabetes Outcome Progression Trial (ADOPT) was conceived in the hope that the seemingly inexorable decline in islet B-cell function described with metformin, sulfonylureas, and insulin in the UK Prospective Diabetes Study (UKPDS) might be stopped or inhibited to a major degree by peroxisome proliferator-activated receptor-γ agonists, in particular rosiglitazone (1,2). It was already well recognized that the rapid early efficacy of sulfonylureas in lowering glucose was not retained to 12 months, and that metformin and thiazolidinediones had slow onset of action over months, so the design of the study necessarily had to enable decline of measures of blood glucose control to be assessed for a considerable period from 1 year onwards. However, the extent (degree and time) to which this early efficacy of the sulfonylureas in protecting against hyperglycemia would persist was not accurately known. The study also provided a good opportunity to compare durability of effect of the three classes of ...
Allelic and genotypic distribution of polymorphisms in diacylglycerol acyltransferase 1 (DGAT1), fatty acid binding protein 4 (FABP4), fatty acid synthase (FASN), and peroxisome proliferator-activated receptor-γ coactivator-1α (PPARGC1A) genes were assessed in 679 Fleckvieh bulls. Single-locus genotype effects and the combined effect of the two polymorphisms within the FASN gene were evaluated for association with the intramuscular fat content and fatty acid profile determined in muscle and subcutaneous fat. The FASN (g.16024GNA) and FASN (g.17924ANG) polymorphisms were significantly associatedmainlywith C14:0, C16:0, and C18:1 n-9 concentrations aswell as with the atherogenic index. The proportion of explained phenotypic variation markedly increased when the effect of a combination of the two polymorphisms within the FASN gene was tested, with the highest values of 8.6% and 14.8%, respectively, observed for C14:0 in muscle and subcutaneous fat. With a focus on improving the fatty acid ...
Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-γ coactivator-1α (Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knockout (MKO) mice and wild-type littermate controls were aged for 2 yr. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 mo of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic ...
The receptor interacting protein-140 (RIP140) is a cofactor for several nuclear receptors and has been involved in the regulation of metabolic and inflammatory genes. We hypothesize that RIP140 may also affect Aβ generation because it modulates the activity of transcription factors previously implicated in amyloid precursor protein (APP) processing, such as peroxisome proliferator-activated receptor-γ (PPARγ). We found that the levels of RIP140 are reduced in Alzheimers disease (AD) postmortem brains compared with healthy controls. In addition, in situ hybridization experiments revealed that RIP140 expression is enriched in the same brain areas involved in AD pathology, such as cortex and hippocampus. Furthermore, we provide evidence using cell lines and genetically modified mice that RIP140 is able to modulate the transcription of certain genes involved in AD pathology, such as β-APP cleaving enzyme (BACE1) and GSK3. Consequently, we found that RIP140 overexpression reduced the generation ...
Abstract There are three isoforms of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA, which promotes mitochondrial biogenesis in skeletal muscles. Compared with PGC-1α-a mRNA, PGC-1α-b or PGC-1α-c mRNA is transcribed by a different exon 1 of the PGC-1α gene. In this study, effects of exercise intensity and 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) on isoform-specific expressions of PGC-1α were…
Abstract Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and…
The peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone (Rosi) appears to provide protection against organ dysfunction during endotoxaemia. We examined the potential benefits of Rosi on skeletal muscle protein maintenance and carbohydrate metabolism during lipopolysaccharide (LPS)-induced endotoxaemia. Sprague-Dawley rats were fed either standard chow (control) or standard chow containing Rosi (8.5±0.1 mg.kg-1.day-1) for two weeks before and during 24 h continuous intravenous infusion of LPS (15 μg.kg-1.h-1) or saline. Rosi blunted LPS-induced increases in muscle tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) mRNA by 70% (P,0.05) and 64% (P,0.01), respectively. Furthermore, Rosi suppressed the LPS-induced reduction in phosphorylated AKT and phosphorylated Forkhead box O (FOXO) 1 protein, as well as the upregulation of muscle RING finger 1 (MuRF1; P,0.01) mRNA, and the LPS-induced increase in 20S proteasome activity (P,0.05). Accordingly, LPS reduced the ...
PPAR Signaling Pathway
Similar to other nuclear hormone receptors, peroxisome proliferator-activated receptors (PPARs) act as ligand-activated transcription factors. When bound to its fatty acid ligand, PPARα forms a heterodimeric complex with the retinoid X receptor (RXR) to regulate transcription. PPARγ is activated by prostaglandins and leukotrienes and regulates the gene expression of proteins involved in the storage of fatty acids. PPARβ is weakly activated by fatty acids, prostaglandins, and leukotrienes. Its physiological ligand has not been identified.
References:
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T0070907 was identified as a potent and selective PPARgamma antagonist. With an apparent binding affinity (concentration at 50% inhibition of [(3)H]rosiglitazone binding or IC(50)) of 1 nm, T0070907 covalently modifies PPARgamma on cysteine 313 in helix 3 of human PPARgamma2. T0070907 blocked PPARgamma function in both cell-based reporter gene and adipocyte differentiation assays. T0070907 is a novel tool for the study of PPARgamma/RXRalpha heterodimer function.
PPAR Research is a peer-reviewed, Open Access journal that publishes original research and review articles on advances in basic research, as well as preclinical and clinical trials, involving Peroxisome Proliferator-Activated Receptors (PPARs).
In this study we report the behavior of two PPAR enantiomeric ligands (R-1 and S-1). Cell-based reporter assays indicate that both enantiomers are dual PPAR/ ligands, being R-1 a full agonist of PPAR and and S-1 a partial agonist of PPAR. 3D-structure analysis of the PPAR ligand binding domain in the complex with the two ligands shows that the suboptimal conformation of helix 12 in the PPAR/S-1 complex is the consequence of a steric hindrance between the ethyl group of the ligand and the Q286 in helix 3. Site-directed mutagenesis confirms that Q286 is a key residue in determining the activity of different ligands. By using FRET assays, we found that the coactivators SRC-1, PGC-1, RIP140, TIF-2 are recruited by R-1, S-1 and rosiglitazone with similar EC50, whereas CBP affinity is higher in the presence of rosiglitazone. Conversely, only S-1 allows the association of the corepressor N-CoR to PPAR as opposed to rosiglitazone and R-1, providing a functional explanation to the partial agonist ...
Pioglitazone HCl is a selective peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist, used to treat diabetes. Buy PPAR inhibitor Pioglitazone HCl (AD-4833, U-72107E) from AbMole BioScience.
PPAR (peroxisome proliferator-activated receptor) family members are among the most widely studied transcription factors. These nuclear receptor proteins exert transcription factor activities and influence multiple cellular events at the molecular level including cell differentiation and development, metabolism and carcinogenesis. This broad spectrum highlights that PPARs are key players of numerous physiological and pathological events. Amongst the PPAR family members, PPARgamma (known to exist in three variant forms) is of particular interest as it is broadly expressed in the mammalian body including all adipose tissue subtypes (white, brown, beige) and also in the intestine, kidneys, pancreas, muscles, placenta, spleen and thymus. As suggested by its expression pattern PPARgamma is indispensable for adipose tissue development, but has also multiple other, context-dependent functions.PPARgamma expression has been reported in several cell types and tissues directly related to immune function (i.e.
AIMS: The Pro12Ala polymorphism in the PPARG gene alters amino acid sequence and has shown consistent association with susceptibility to Type 2 diabetes in several populations. The present study makes use of large, well-characterized case-control resources to enhance understanding of this susceptibility effect by examining related traits, such as body mass index (BMI), waist-hip ratio and age at diagnosis. METHODS: The Pro12Ala variant was genotyped in two UK case samples, ascertained for positive family history and/or early onset of Type 2 diabetes (combined n=971); and in 1257 ethnically matched control subjects. RESULTS: There were significant associations of the Pro12Ala single nucleotide polymorphism (SNP) genotypes with diabetes in both case-control comparisons (P=0.025 and P=0.039). Comparing individuals homozygous for the Pro allele, with those carrying an Ala allele, the combined odds ratio for diabetes was 1.40 (95% CIs, 1.12-1.76, P=0.0031). There was no association between the variant and