Peroxisome proliferator-activated receptors in vascular biology and atherosclerosis: Emerging insights for evolving paradigms
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Peroxisome proliferator-activated receptor gamma agonists have been proposed as breast cancer preventives. Individuals who carry a mutated copy of BRCA1 , DNA repair-associated gene, are at increased risk for development of breast cancer. Published data in the field suggest there could be interactions between peroxisome proliferator-activated receptor gamma and BRCA1 that could influence the activity of peroxisome proliferator-activated receptor gamma agonists for prevention. This review explores these possible interactions between peroxisome proliferator-activated receptor gamma, peroxisome proliferator-activated receptor gamma agonists and BRCA1 and discusses feasible experimental directions to provide more definitive information on the potential connections.
Peroxisome proliferator
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Peroxisome proliferator-activated receptors are ligand-activated intracellular transcription factors that have been implicated in important biological processes such as inflammation, tissue remodeling and atherosclerosis. Emerging information also implicates peroxisome proliferator-activated receptors in oncogenesis. Peroxisome proliferator-activated receptor γ, the best studied of the peroxisome proliferator-activated receptors, modulates the proliferation and apoptosis of many cancer cell types, and it is expressed in many human tumors including lung, breast, colon, prostate and bladder. Natural and synthetic agents capable of activating peroxisome proliferator-activated receptor γ have been found to inhibit cancer cell growth in vitro and in animal models. These agents, however, are not specific and both peroxisome proliferator-activated receptor γ-dependent and peroxisome proliferator-activated receptor γ-independent pathways involved in their effects have been identified. Together, these studies, coupled with a few clinical trials, suggest that peroxisome proliferator-activated receptor γ is a novel target for the development of new and effective anticancer therapies.
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Purpose of review The thiazolidinediones are agonists for peroxisome proliferator-activated receptor-γ, and promote insulin sensitization and improve dyslipidemia in patients with type II diabetes mellitus. Peroxisome proliferator-activated receptor-γ transduces its actions by binding to common consensus response elements called peroxisome proliferator-activated receptor-response elements, thus modifying expression of numerous genes. Peroxisome proliferator-activated receptor-γ is widely expressed, including in macrophages and vascular smooth muscle cells. I will review recent novel insights into peroxisome proliferator-activated receptor-γ agonist actions. Recent findings The thiazolidinediones have beneficial effects in humans with type II diabetes related in part to improvement of dysmetabolic syndrome, and also have beneficial effects on progressive renal damage in animal models of diabetic nephropathy and in models with severe hyperlipidemia. Peroxisome proliferator-activated receptor-γ agonists also have direct benefits on progressive renal injury independent of altering the dysmetabolic profile. Summary We will review selected evidence of actions of peroxisome proliferator-activated receptor-γ agonists beyond metabolism, focusing on experimental work, and examine interactions with other key profibrotic mediators, including transforming growth factor-β and the renin–angiotensin system.
Troglitazone
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Peroxisome proliferator-activated receptor gamma (PPARg), is a ligand-activated transcription factor which regulates gene expression. PPARg is highly expressed in the colon, inhibiting the NF-kB activated pathway, an anti-inflammatory effect of PPARg is observed. 5-aminosalicylic acid (5-ASA) is a PPARg ligand which can induce inflammatory genes repression.
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The peroxisome-proliferator-activated receptor y is a member of the nuclear receptor superfamily that functions as a key transcriptional regulator of cell differentiation and lipid metabolism. In addition, peroxisome-proliferator-activated receptor y is now recognized to be the biological receptor for the thiazolidinedione class of antidiabetic drugs, which includes troglitazone and rosiglitazone. Recent evidence indicates that peroxisome-proliferator-activated receptor y is expressed at high levels in macrophages, including the foam cells of atherosclerotic lesions. Oxidized low-density lipoprotein, which plays a central role in lesion development, can activate peroxisome-proliferator-activated receptor y by providing the cell with oxidized fatty acid ligands of the receptor. The elucidation of a peroxisome-proliferator-activated receptor y signalling pathway in macrophages provides a mechanism by which oxidized lipids may directly regulate gene expression in the context of the atherosclerotic lesion. A number of potential target genes for peroxisome-proliferator-activated receptor y in these cells have been identified. Some, such as the type B scavenger receptor CD36 are induced by peroxisome-proliferator-activated receptor y ligands, whereas others, such as scavenger receptor type A, inducible nitric oxide synthetase and certain cytokines, are repressed. Given the widespread clinical use of thiazolidinediones, it is important to consider the influence of these drugs on the risk of atherosclerosis. The net effect of peroxisome-proliferator-activated receptor y ligands on the atherogenic process is likely to reflect a balance between local effects in the artery wall and systemic effects on lipid metabolism.
Troglitazone
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Objective: The Angiotensin-II receptor blocker telmisartan and sulfonylurea glimepiride may have clinical usefulness as partial agonists of PPARg.We investigated additive and antagonistic effects among combinations of telmisartan, glimepiride, and the Thiazolidinedione (TZD) selective PPARg agonist pioglitazone on transcriptional activity of PPARg.Materials/Methods: The receptors of pCMX-PPARg and pCMX-RXR, and PPRE-Luc reporter gene were transfected into CV1 cells, and treated with following agents, and luciferace assay was performed.Moreover, mammalian two-hybrid assay was done using GAL4 responsive reporter tk-MH100(UAS)×4-Luc and the chimeric receptor GAL4-PPARg.Results: Telmisartan increased transactivation of PPARg dose dependently.Activation by telmisartan 10 µM was 58.8% of that by pioglitazone 10 µM.Glimepiride also increased transactivation of PPARg dose dependently.Activation by glimepiride 10 µM was 49.8% of that by pioglitazone 10 µM.Addition of telmisartan 5 µM significantly enhanced transactivation by glimepiride 10 and 50 µM.Moreover, addition of pioglitazone 0.5 µM significantly enhanced transactivation by glimepiride 10 and 50 µM.Mammalian two-hybrid assay showed additive effect between glimepiride and telmisartan on binding of SRC-1 to PPARg.On the other hand, addition of glimepiride 10 and 50 µM reduced transactivation by pioglitazone 5 µM to 74% and 70%, respectively.Conclusion: Partial agonists of PPARg additively enhanced transactivation by other agonists, whereas high concentration of partial agonists reduced transactivation by full agonist antagonistically.
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Dyslipidemia
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PPARGC1A
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Peroxisome proliferator-activated receptors mediate the transcriptional effects of fatty acids and fatty acid metabolites and regulate many physiological functions including development and metabolism. The roles of peroxisome proliferator-activated receptor alpha and gamma isotypes have been well established, while the functions of the third member of the family, peroxisome proliferator-activated receptor delta, remained unclear until very recently. This review focuses on the physiological functions of the nuclear receptor and especially on its roles in the control of fatty acid metabolism.We review very recent data demonstrating that peroxisome proliferator-activated receptor delta plays a central role in the regulation of fatty acid oxidation in several tissues, such as skeletal muscle and adipose tissue, and also that the nuclear receptor is involved in cholesterol metabolism.Use of potent and specific peroxisome proliferator-activated receptor delta agonists and appropriate transgenic animal models revealed the importance of this nuclear receptor in regulation of fatty acid catabolism in skeletal muscle and other tissues. It also indicated the potential of peroxisome proliferator-activated receptor delta as a therapeutic target in pathologies such as metabolic syndrome. However, the effects of peroxisome proliferator-activated receptor delta activation in atherosclerosis and the control of cell proliferation remain to be established.
Fatty Acid Metabolism
Catabolism
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