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Walter Wahli - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome Proliferator-Activated Receptors as Molecular Links between Caloric Restriction and Circadian Rhythm
Nutrients, 2020Co-Authors: Kalina Duszka, Walter WahliAbstract:The circadian rhythm plays a chief role in the adaptation of all bodily processes to internal and environmental changes on the daily basis. Next to light/dark phases, feeding patterns constitute the most essential element entraining daily oscillations, and therefore, timely and appropriate restrictive diets have a great capacity to restore the circadian rhythm. One of the restrictive nutritional approaches, caloric restriction (CR) achieves stunning results in extending health span and life span via coordinated changes in multiple biological functions from the molecular, cellular, to the whole-body levels. The main molecular pathways affected by CR include mTOR, insulin signaling, AMPK, and sirtuins. Members of the family of nuclear Receptors, the three Peroxisome Proliferator-Activated Receptors (PPARs), PPARα, PPARβ/δ, and PPARγ take part in the modulation of these pathways. In this non-systematic review, we describe the molecular interconnection between circadian rhythm, CR-associated pathways, and PPARs. Further, we identify a link between circadian rhythm and the outcomes of CR on the whole-body level including oxidative stress, inflammation, and aging. Since PPARs contribute to many changes triggered by CR, we discuss the potential involvement of PPARs in bridging CR and circadian rhythm.
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Peroxisome Proliferator-Activated Receptors and Caloric Restriction-Common Pathways Affecting Metabolism, Health, and Longevity
Cells, 2020Co-Authors: Kalina Duszka, Hervé Guillou, András Gregor, Jürgen König, Walter WahliAbstract:Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with Peroxisome Proliferator-Activated Receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.
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Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
Cells, 2020Co-Authors: Anne Fougerat, Alexandra Montagner, Nicolas Loiseau, Hervé Guillou, Walter WahliAbstract:Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear Receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.
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Glycogen synthase 2 is a novel target gene of Peroxisome Proliferator-Activated Receptors.
Cellular and Molecular Life Sciences, 2007Co-Authors: Stéphane Mandard, Beatrice Desvergne, Walter Wahli, Rinke Stienstra, Pascal Escher, Nguan Soon Tan, Insook Kim, Frank Gonzalez, Michael Müller, Sander KerstenAbstract:Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARalpha, PPARbeta/delta and PPARgamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPARalpha-/-, PPARbeta/delta-/- and PPARgamma+/- mice. Furthermore, synthetic PPARbeta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARalpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4alpha). In adipose tissue, which does not express HNF4alpha, DR-1prom is occupied by PPARbeta/delta and PPARgamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4alpha is mediated by two distinct response elements.
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Glycogen synthase 2 is a novel target gene of Peroxisome Proliferator-Activated Receptors
Cellular and Molecular Life Sciences, 2007Co-Authors: S. Mandard, Beatrice Desvergne, Walter Wahli, Rinke Stienstra, Pascal Escher, Nguan Soon Tan, Insook Kim, Michael Müller, F. J. Gonzalez, S. KerstenAbstract:Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARα, PPARβ/δ and PPARγ. Expression of Gys-2 is significantly reduced in adipose tissue of PPARα-/-, PPARβ/δ-/- and PPARγ+/- mice. Furthermore, synthetic PPARβ/δ, and γ agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARα deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4α). In adipose tissue, which does not express HNF4α, DR-1prom is occupied by PPARβ/δ and PPARγ, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4α is mediated by two distinct response elements.
Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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Fibrates, glitazones, and Peroxisome Proliferator-Activated Receptors
Arteriosclerosis Thrombosis and Vascular Biology, 2010Co-Authors: Fanny Lalloyer, Bart StaelsAbstract:Several decades ago, fibrates were approved for the treatment of dyslipidemia, whereas thiazolidinediones were screened in animal models to improve glucose homeostasis and were subsequently developed for the treatment of type 2 diabetes mellitus. Relatively recently, these drugs were found to act via Peroxisome proliferator–activated Receptors, nuclear Receptors that control lipid metabolism and glucose homeostasis. In this historical perspective, we discuss the history of discovery of the Peroxisome proliferator–activated Receptors, from the clinical development of their agonists to the subsequent discovery of these Receptors and their mechanisms of action, to finally evoke possibilities of targeted pharmacology for future development of selective Peroxisome proliferator–activated receptor modulators.
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History of Discovery Fibrates, Glitazones, and Peroxisome Proliferator-Activated Receptors
2010Co-Authors: Fanny Lalloyer, Bart StaelsAbstract:Several decades ago, fibrates were approved for the treatment of dyslipidemia, whereas thiazolidinediones were screened in animal models to improve glucose homeostasis and were subsequently developed for the treatment of type 2 diabetes mellitus. Relatively recently, these drugs were found to act via Peroxisome Proliferator-Activated Receptors, nuclear Receptors that control lipid metabolism and glucose homeostasis. In this historical perspective, we discuss the history of discovery of the Peroxisome Proliferator-Activated Receptors, from the clinical development of their agonists to the subsequent discovery of these Receptors and their mechanisms of action, to finally evoke possibilities of targeted pharmacology for future development of selective Peroxisome Proliferator-Activated receptor modulators. (Arterioscler Thromb Vasc Biol. 2010;30:894-899.)
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Peroxisome proliferator activated Receptors in reproductive tissues from gametogenesis to parturition
Journal of Endocrinology, 2006Co-Authors: Pascal Froment, Bart Staels, F. Gizard, D. Defever, Joëlle Dupont, Philippe MongetAbstract:Peroxisome Proliferator-Activated Receptors (PPAR, PPAR/ and PPAR) are a family of nuclear Receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPAR, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPAR in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPAR. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other ‘insulin sensitizer’ molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.
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Peroxisome Proliferator-Activated Receptors in reproductive tissues: from gametogenesis to parturition
Journal of Endocrinology, 2006Co-Authors: Pascal Froment, Bart Staels, F. Gizard, D. Defever, Joëlle Dupont, Philippe MongetAbstract:Peroxisome Proliferator-Activated Receptors (PPAR alpha, PPAR beta/delta and PPAR gamma) are a family of nuclear Receptors that are activated by binding of natural ligands, such as polyunsaturated fatty acids or by synthetic ligands. Synthetic molecules of the glitazone family, which bind to PPAR gamma, are currently used to treat type II diabetes and also to attenuate the secondary clinical symptoms frequently associated with insulin resistance, including polycystic ovary syndrome (PCOS). PPARs are expressed in different compartments of the reproductive system (hypothalamus, pituitary, ovary, uterus and testis). Conservative functions of PPARs in mammalian species could be suggested through several in vivo and in vitro studies, especially in the ovary and during placental development. Several groups have described a strong expression of PPAR gamma in ovarian granulosa cells, and glitazones modulate granulosa cell proliferation and steroidogenesis in vitro. All these recent data raise new questions about the biologic actions of PPARs in reproduction and their use in therapeutic treatments of fertility troubles such as PCOS or endometriosis. In this review, we first describe the roles of PPARs in different compartments of the reproductive axis (from male and female gametogenesis to parturition), with a focus on PPAR gamma. Secondly, we discuss the possible molecular mechanisms underlying the effect of glitazones on PCOS. Like other 'insulin sensitizer' molecules, such as metformin, glitazones may in fact act directly on ovarian cells. Finally, we discuss the eventual actions of PPARs as mediators of environmental toxic substances for reproductive function.
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Peroxisome proliferator activated Receptors and atherogenesis regulators of gene expression in vascular cells
Circulation Research, 2004Co-Authors: Nikolaus Marx, Jean-charles Fruchart, Helene Duez, Bart StaelsAbstract:A large body of data gathered over the past couple of years has identified the Peroxisome Proliferator-Activated Receptors (PPAR) α, γ, and β/δ as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARα, γ, and β/δ subtypes are ≈60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARα is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARα controls expression of genes implicated in lipid metabolism. PPARγ, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARγ include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyΔ 12,14 -prostaglandin J 2 , and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARβ/δ are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARβ/δ stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARα and PPARγ activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARβ/δ agonists on atherogenesis. Given the widespread use of PPARα and PPARγ agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is not only of basic interest but also has important clinical implications. This review will focus on the role of PPARs in the vasculature and summarize the present understanding of their effects on atherogenesis and its cardiovascular complications.
Beatrice Desvergne - One of the best experts on this subject based on the ideXlab platform.
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Glycogen synthase 2 is a novel target gene of Peroxisome Proliferator-Activated Receptors.
Cellular and Molecular Life Sciences, 2007Co-Authors: Stéphane Mandard, Beatrice Desvergne, Walter Wahli, Rinke Stienstra, Pascal Escher, Nguan Soon Tan, Insook Kim, Frank Gonzalez, Michael Müller, Sander KerstenAbstract:Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARalpha, PPARbeta/delta and PPARgamma. Expression of Gys-2 is significantly reduced in adipose tissue of PPARalpha-/-, PPARbeta/delta-/- and PPARgamma+/- mice. Furthermore, synthetic PPARbeta/delta, and gamma agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARalpha deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4alpha). In adipose tissue, which does not express HNF4alpha, DR-1prom is occupied by PPARbeta/delta and PPARgamma, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4alpha is mediated by two distinct response elements.
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Glycogen synthase 2 is a novel target gene of Peroxisome Proliferator-Activated Receptors
Cellular and Molecular Life Sciences, 2007Co-Authors: S. Mandard, Beatrice Desvergne, Walter Wahli, Rinke Stienstra, Pascal Escher, Nguan Soon Tan, Insook Kim, Michael Müller, F. J. Gonzalez, S. KerstenAbstract:Glycogen synthase 2 (Gys-2) is the ratelimiting enzyme in the storage of glycogen in liver and adipose tissue, yet little is known about regulation of Gys-2 transcription. The Peroxisome Proliferator-Activated Receptors (PPARs) are transcription factors involved in the regulation of lipid and glucose metabolism and might be hypothesized to govern glycogen synthesis as well. Here, we show that Gys-2 is a direct target gene of PPARα, PPARβ/δ and PPARγ. Expression of Gys-2 is significantly reduced in adipose tissue of PPARα-/-, PPARβ/δ-/- and PPARγ+/- mice. Furthermore, synthetic PPARβ/δ, and γ agonists markedly up-regulate Gys-2 mRNA and protein expression in mouse 3T3-L1 adipocytes. In liver, PPARα deletion leads to decreased glycogen levels in the refed state, which is paralleled by decreased expression of Gys-2 in fasted and refed state. Two putative PPAR response elements (PPREs) were identified in the mouse Gys-2 gene: one in the upstream promoter (DR-1prom) and one in intron 1 (DR-1int). It is shown that DR-1int is the response element for PPARs, while DR-1prom is the response element for Hepatic Nuclear Factor 4 alpha (HNF4α). In adipose tissue, which does not express HNF4α, DR-1prom is occupied by PPARβ/δ and PPARγ, yet binding does not translate into transcriptional activation of Gys-2. Overall, we conclude that mouse Gys-2 is a novel PPAR target gene and that transactivation by PPARs and HNF4α is mediated by two distinct response elements.
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from molecular action to physiological outputs Peroxisome proliferator activated Receptors are nuclear Receptors at the crossroads of key cellular functions
Progress in Lipid Research, 2006Co-Authors: Jerome N Feige, Laurent Gelman, Beatrice Desvergne, Liliane Michalik, Walter WahliAbstract:Peroxisome Proliferator-Activated Receptors (PPARs) compose a family of three nuclear Receptors which act as lipid sensors to modulate gene expression. As such, PPARs are implicated in major metabolic and inflammatory regulations with far-reaching medical consequences, as well as in important processes controlling cellular fate. Throughout this review, we focus on the cellular functions of these Receptors. The molecular mechanisms through which PPARs regulate transcription are thoroughly addressed with particular emphasis on the latest results on corepressor and coactivator action. Their implication in cellular metabolism and in the control of the balance between cell proliferation, differentiation and survival is then reviewed. Finally, we discuss how the integration of various intra-cellular signaling pathways allows PPARs to participate to whole-body homeostasis by mediating regulatory crosstalks between organs.
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Peroxisome proliferator activated Receptors and cancers complex stories
Nature Reviews Cancer, 2004Co-Authors: Liliane Michalik, Beatrice Desvergne, Walter WahliAbstract:Peroxisome-Proliferator-Activated Receptors (PPARs) are nuclear hormone Receptors that mediate the effects of fatty acids and their derivatives at the transcriptional level. Through these pathways, PPARs can regulate cell proliferation, differentiation and survival, so controlling carcinogenesis in various tissues. But what are the links between each PPAR isotype and carcinogenesis and what is the relevance of these findings to human pathology and therapy?
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Peroxisome proliferator activated Receptors a nuclear receptor signaling pathway in lipid physiology
Annual Review of Cell and Developmental Biology, 1996Co-Authors: Thomas Lemberger, Beatrice Desvergne, Walter WahliAbstract:▪ Abstract Peroxisome Proliferator-Activated Receptors (PPARs) are lipid-activated transcription factors that belong to the steroid/thyroid/retinoic acid receptor superfamily. All their characterized target genes encode proteins that participate in lipid homeostasis. The recent finding that antidiabetic thiazolidinediones and adipogenic prostanoids are ligands of one of the PPARs reveals a novel signaling pathway that directly links these compounds to processes involved in glucose homeostasis and lipid metabolism including adipocyte differentiation. A detailed understanding of this pathway could designate PPARs as targets for the development of novel efficient treatments for several metabolic disorders.
Joorg Reichrath - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome Proliferator-Activated Receptors (PPARs) and the Human Skin
American Journal of Clinical Dermatology, 2008Co-Authors: Pi Sertznig, Markus Seifert, Wolfgang Tilgen, Joorg ReichrathAbstract:Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders. It has been shown that in inflammatory skin disorders, including hyperproliferative psoriatic epidermis and the skin of patients with atopic dermatitis, the expression of both PPARα and PPARγ is decreased. This observation suggests the possibility that PPARα and PPARγ activators, or compounds that positively regulate PPAR gene expression, may represent novel NSAIDs for the topical or systemic treatment of common inflammatory skin diseases such as atopic dermatitis, psoriasis, and allergic contact dermatitis. Moreover, recent findings indicate that PPAR-signaling pathways may act as a promising therapeutic target for the treatment of hyperproliferative skin diseases including skin malignancies. Studies in non-diabetic patients suggest that oral thiazolidinediones, which are synthetic ligands of PPARγ, not only exert an antidiabetic effect but also may be beneficial for moderate chronic plaque psoriasis by suppressing proliferation and inducing differentiation of keratinocytes; furthermore, they may even induce cell growth arrest, apoptosis, and terminal differentiation in various human malignant tumors. It has been reported that PPARα immunoreactivity is reduced in human keratinocytes of squamous cell carcinoma (SCC) and actinic keratosis (AK), while PPARδ appears to be upregulated. Additionally, the microvessel density is significantly higher in AK and SCC that express high levels of PPARδ. PPARδ has been demonstrated to have an anti-apoptotic role and to maintain survival and differentiation of epithelial cells, whereas PPARα and PPARγ activators induce differentiation and inhibit proliferation and regulate apoptosis. In melanoma, the growth inhibitory effect of PPARγ activation is independent of apoptosis and seems to occur primarily through induction of cell cycle arrest in the G1 phase of the cell cycle or induction of re-differentiation. PPARα activation causes inhibition of migration of melanoma cells and anchorage-independent growth, whereas primary tumor growth remains unaltered. In clinical trials of gemfibrozil, a PPARα ligand, significantly fewer patients treated with this lipid-lowering drug were diagnosed with melanoma as compared to those in the control group. In conclusion, an increasing body of evidence indicates that PPAR signaling pathways may represent interesting therapeutic targets for a broad variety of skin disorders, including inflammatory skin diseases such as psoriasis and atopic dermatitis, and skin malignancies.
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Peroxisome proliferator activated Receptors ppars and the human skin importance of ppars in skin physiology and dermatologic diseases
American Journal of Clinical Dermatology, 2008Co-Authors: Pi Sertznig, M Seife, Wolfgang Tilge, Joorg ReichrathAbstract:Peroxisome Proliferator-Activated Receptors (PPARs) are members of the nuclear receptor superfamily that regulate lipid, glucose, and amino acid metabolism. More recently, PPARs and corresponding ligands have been shown in skin and other organs to regulate important cellular functions, including cell proliferation and differentiation, as well as inflammatory responses. These new functions identify PPARs and corresponding ligands as potential targets for the treatment of various skin diseases and other disorders.
Ernesto L. Schiffrin - One of the best experts on this subject based on the ideXlab platform.
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Peroxisome proliferator activated Receptors in vascular biology molecular mechanisms and clinical implications
Vascular Pharmacology, 2006Co-Authors: Rhian M Touyz, Ernesto L. SchiffrinAbstract:Peroxisome Proliferator-Activated Receptors (PPAR)α, γ and β/δ belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARα, γ and β/δ subtypes have significant differences in their ligand and gene specificities. PPARα is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARγ is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Δ12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARγ is a key regulator of glucose homeostasis and adipogenesis. PPARβ/δ ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARα (fibrates) and PPARγ (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease.
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Peroxisome Proliferator-Activated Receptors and cardiovascular remodeling
American journal of physiology. Heart and circulatory physiology, 2004Co-Authors: Ernesto L. SchiffrinAbstract:Peroxisome Proliferator-Activated Receptors (PPARs) are nuclear Receptors that heterodimerize with the retinoid X receptor and then modulate the function of many target genes. Three PPARs are known...