Multifaceted roles of peroxisome proliferator-activated receptors (PPARs) at the cellular and whole organism levels.

Chronic disorders, such as obesity, diabetes, inflammation, non-alcoholic fatty liver disease and atherosclerosis, are related to alterations in lipid and glucose metabolism, in which peroxisome proliferator-activated receptors (PPAR)α, PPARβ/δ and PPARγ are involved. These receptors form a subgroup of ligand-activated transcription factors that belong to the nuclear hormone receptor family. This review discusses a selection of novel PPAR functions identified during the last few years. The PPARs regulate processes that are essential for the maintenance of pregnancy and embryonic development. Newly found hepatic functions of PPARα are the mediation of female-specific gene repression and the protection of the liver from oestrogen induced toxicity. PPARα also controls lipid catabolism and is the target of hypolipidaemic drugs, whereas PPARγ controls adipocyte differentiation and regulates lipid storage; it is the target for the insulin sensitising thiazolidinediones used to treat type 2 diabetes. Activation of PPARβ/δ increases lipid catabolism in skeletal muscle, the heart and adipose tissue. In addition, PPARβ/δ ligands prevent weight gain and suppress macrophage derived inflammation. In fact, therapeutic benefits of PPAR ligands have been confirmed in inflammatory and autoimmune diseases, such as encephalomyelitis and inflammatory bowel disease. Furthermore, PPARs promote skin wound repair. PPARα favours skin healing during the inflammatory phase that follows injury, whilst PPARβ/δ enhances keratinocyte survival and migration. Due to their collective functions in skin, PPARs represent a major research target for our understanding of many skin diseases. Taken altogether, these functions suggest that PPARs serve as physiological sensors in different stress situations and remain valuable targets for innovative therapies.

Be fit or be sick: peroxisome proliferator-activated receptors are down the road.

Investigating metabolism by unveiling the functions of the nuclear receptors peroxisome proliferator-activated receptors (PPARs) in the numerous intricate pathways ensuring energy homeostasis and fitness has been extremely rewarding. Major lines of research were initially determined by the first-characterized crucial roles of PPARalpha in fatty oxidation and of PPARgamma in adipocyte differentiation and lipid storage. Today, the molecular bases of the functional links between glucose, lipid, and protein metabolism, under the important but nonexclusive control of PPARalpha and PPARgamma, are starting to be uncovered. In addition, in the last couple of years evidence has been provided for an important role of PPARbeta (delta) in lipid metabolism. Inevitably, such actors of metabolic homeostasis are implicated in the physiopathology of complex metabolic disorders, such as those constituting the metabolic syndrome, resulting in atherosclerosis and cardiovascular diseases. This review presents a summary of the recent findings on their dual involvement in health and disease.

Peroxisome proliferator-activated receptors (PPARs): from metabolic control to epidermal wound healing.

Peroxisome proliferator-activated receptors control many cellular and metabolic processes. They are transcription factors belonging to the family of ligand-inducible nuclear receptors. Three isotypes called PPARalpha, PPARbeta/delta and PPARgamma have been identified in lower vertebrates and mammals. They display differential tissue distribution and each of the three isotypes fulfills specific functions. PPARalpha and PPARgamma control energy homoeostasis and inflammatory responses. Their activity can be modulated by drugs such as the hypolipidaemic fibrates and the insulin sensitising thiazolidinediones (pioglitazone and rosiglitazone). Thus, these receptors are involved in the control of chronic diseases such as diabetes, obesity, and atherosclerosis. Little is known about the main function of PPARbeta, but it has been implicated in embryo implantation, tumorigenesis in the colon, reverse cholesterol transport, and recently in skin wound healing. Here, we present recent developments in the PPAR field with particular emphasis on both the function of PPARs in lipid metabolism and energy homoeostasis (PPARalpha and PPARgamma), and their role in epidermal maturation and skin wound repair (PPARalpha and PPARbeta).

Peroxisome proliferator-activated receptors A link between endocrinology and nutrition?

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily like the steroid, thyroid, or retinoid hormone receptors, which are ligand-activated transcription factors regulating gene expression. PPARs mediate the induction of the enzymes of the peroxisomal and microsomal fatty-acid oxidation pathways by hypolipidemic drugs such as clofibrate and are probably also involved in the gene expression of other lipid-metabolism-associated proteins that are controlled by fibrate hypolipidemic drugs. That PPARs play an important role in the regulation of lipid metabolism is reinforced by the discovery of their activation by physiologic concentrations of fatty acids. This observation raises the question of whether fatty acids are ligands of PPARs, which would imply that nutritional fatty acids can act like hormones.

Peroxisome proliferator-activated receptors and lipid metabolism.

PPARs are nuclear hormone receptors which, like the retinoid, thyroid hormone, vitamin D, and steroid hormone receptors, are ligand-activated transcription factors mediating the hormonal control of gene expression. Two lines of evidence indicate that PPARs have an important function in fatty acid metabolism. First, PPARs are activated by hypolipidemic drugs and physiological concentrations of fatty acids, and second, PPARs control the peroxisomal beta-oxidation pathway of fatty acids through transcriptional induction of the gene encoding the acyl-CoA oxidase (ACO), which is the rate-limiting enzyme of the pathway. Furthermore, the PPAR signaling pathway appears to converge with the 9-cis retinoic acid receptor (RXR) signaling pathway in the regulation of the ACO gene because heterodimerization between PPAR and RXR is essential for in vitro binding to the PPRE and because the strongest stimulation of this gene is observed when both receptors are exposed simultaneously to their activators. Thus, it appears that PPARs are involved in the 9-cis retinoic acid signaling pathway and that they play a pivotal role in the hormonal control of lipid metabolism.

Glycogen synthase 2 is a novel target gene of peroxisome proliferator-activated receptors.

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.

The peroxisome proliferator-activated receptors at the cross-road of diet and hormonal signalling.

The peroxisome proliferator-activated receptors (PPARs) are members of the steroid/thyroid nuclear receptor superfamily of ligand-activated transcription factors. To date, three isotypes have been identified, alpha, beta and gamma, encoded by three different genes. The alpha isotype is expressed at high levels in the liver where it has a role in lipid oxidation. Its expression and activity follow a diurnal rhythm that parallels the circulating levels of corticosterone in the bloodstream. The gamma isotype on the other hand, is mainly expressed in adipose tissue and has a critical role in adipocyte differentiation and lipid storage. The function of the ubiquitously expressed isotype, PPAR beta, remains to be determined. Besides fulfilling different roles in lipid metabolism, the different PPAR isotypes also have different ligand specificities. A new approach to identify ligands was developed based on the ligand-dependent interaction of PPAR with the recently characterized co-activator SRC-1. This so-called CARLA assay has allowed the identification of fatty acids and eicosanoids as PPAR ligands. Although the evidence clearly links PPAR isotypes to distinct functions, the molecular basis for this isotype-specificity is still unclear. All three isotypes are able to bind the same consensus response element, formed by a direct repeat of two AGGTCA hexamers separated by one base, though with different affinities. We recently demonstrated that besides the core DR-1 element, the 5' flanking sequence should be included in the definition of a PPRE. Interestingly, the presence of this flanking sequence is of particular importance in the context of PPAR alpha binding. Moreover, it reflects the polarity of the PPAR-RXR heterodimer on DNA, with PPAR binding to the 5' half-site and RXR binding to the 3' half-site. This unusual polarity may confer unique properties to the bound heterodimer with respect to ligand binding and interaction with co-activators and corepressors.

Selective cooperation between fatty acid binding proteins and peroxisome proliferator-activated receptors in regulating transcription.

Lipophilic compounds such as retinoic acid and long-chain fatty acids regulate gene transcription by activating nuclear receptors such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptors (PPARs). These compounds also bind in cells to members of the family of intracellular lipid binding proteins, which includes cellular retinoic acid-binding proteins (CRABPs) and fatty acid binding proteins (FABPs). We previously reported that CRABP-II enhances the transcriptional activity of RAR by directly targeting retinoic acid to the receptor. Here, potential functional cooperation between FABPs and PPARs in regulating the transcriptional activities of their common ligands was investigated. We show that adipocyte FABP and keratinocyte FABP (A-FABP and K-FABP, respectively) selectively enhance the activities of PPARgamma and PPARbeta, respectively, and that these FABPs massively relocate to the nucleus in response to selective ligands for the PPAR isotype which they activate. We show further that A-FABP and K-FABP interact directly with PPARgamma and PPARbeta and that they do so in a receptor- and ligand-selective manner. Finally, the data demonstrate that the presence of high levels of K-FABP in keratinocytes is essential for PPARbeta-mediated induction of differentiation of these cells. Taken together, the data establish that A-FABP and K-FABP govern the transcriptional activities of their ligands by targeting them to cognate PPARs in the nucleus, thereby enabling PPARs to exert their biological functions.

Activité physique et prévention de l'athérosclérose : mise en évidence de l'implication des PPAR (Peroxisome Proliferaor-Activated Receptor) dans la cardioprotection induite par l'exercice physique soumis ou volontaire chez la souris ApoE-/-.

L'athérosclérose est un processus inflammatoire chronique à l'origine des accidents cardiovasculaires qui constitue l'une des premières causes de mortalité en France. L'inflammation est le facteur essentiel dans l'initiation, la progression et l'instabilité des lésions athéromateuses à l'origine des accidents aigus. Les données récentes suggèrent que l'activation des récepteurs nucléaires PPAR (Peroxysome-Proliferator Activated Receptor) par des ligands pharmacologiques prévient le développement et la progression de l'athérosclérose et diminue de manière importante la mortalité cardiovasculaire. À côté de ces traitements pharmacologiques, l'exercice physique prévient aussi la mortalité cardiovasculaire de manière significative. L'objectif de notre premier travail a été d'explorer les effets de l'exercice physique de natation, sur le déve¬loppement des lésions athéromateuses d'une part et d'autre part, sur l'expression des récepteurs nucléaires PPAR. Nos résultats montrent que l'exercice physique de natation diminue la progression de l'athérosclérose et stimule l'expression des PPAR-γ vasculaires. De manière intéressante, lorsque le PPAR-γ est inhibé avec l'antagoniste BADGE, les effets antiathérogènes de l'exercice physique sont abolis. L'hypertension est à l'origine des complications graves telles que la rupture de plaque d'athérosclérose. L'objectif de notre deuxième travail a été d'explorer l'implication des PPAR dans la progression et la stabilité des lésions athéromateuses chez des souris ApoE-/- hypercholestérolemiques et hypertendues (2K1C), soumises à des exercices physiques (volontaire ou imposé) ou traités avec le telmisartan, un antihypertenseur. Nos résultats montrent que l'exercice physique possède différents mécanismes protecteurs. De manière similaire, l'exercice physique favorise la stabilité de lésions athéromateuses de manière comparable au traitement pharmacologique. De plus, nos résultats montrent que les souris traitées avec l'exercice imposé ou le telmisartan présentent un mécanisme comparable qui permet de réduire significativement l'expression des cytokines pro-inflammatoire et d'activer les PPAR-γ vasculaires. L'exercice volontaire favorise l'expression des marqueurs des macrophages alternatifs M2 et des cytokines anti-inflammatoires (CD 206, IL-1 Ra). L'exercice volontaire diminue significativement l'extension des lésions athéromateuses de manière comparable au telmisartan. Ces résultats montrent que l'exercice physique volontaire et l'exercice physique imposé ont deux mécanismes d'actions distincts. De plus, la surexpression des M2 en réponse à l'exercice volontaire modifie la balance inflammatoire en faveur des M2. Ce renversement de la balance au profit des macrophages alternatifs M2 est significativement corrélé à la diminution de la progression des lésions athéromateuses. Les exercices imposé et volontaire possèdent des mécanismes d'action distincts. L'exercice soumis diminue l'expression des cytokines pro-inflammatoires tandis que l'exercice volontaire augmente l'expression des cytokines anti-inflammatoires et favorise un phénotype anti-inflammatoire des macrophages M2 qui s'accompagne d'une réduction des lésions athéromateuses. - Atherosclerosis is a complex inflammatory process, leading cause of morbidity and mortality in France. Inflammation is essential in initiation, progression and atherosclerosis plaque destabilization leading to acute cardiovascular events. Recent studies suggest that pharmacological PPAR activation prevents ΑΤΗ développement and progression and decreased cardiovascular mortality. Compared to pharmacological treatment, physical exercise also significantly prevents cardiovascular mortality. The aim of the first study was to investigate the influence of physical exercise on ATS development and PPAR expression in arterial wall. Our results had shown that physical exercise decrease ΑΤΗ progression and increase PPAR-γ expression in arterial wall. Interestingly, PPAR-γ inhibition with BADGE, a PPAR-γ antagonist abolishes these antiatherogenic effects. Hypertension increase ΑΤΗ complication such as plaque rupture. The aim of the second study were to inves¬tigate PPAR-γ implication in progression and stabilization of ΑΤΗ lesions in hypercholesterolemic and hypertensive ApoE-/- mice (2K1C) submitted to different exercises (voluntary wheel running and submitted treadmill running) or treated with telmisartan an anti-hypertensive drug. Our results shown that, physical exercise prevents ATS cardiovascular events by several mechanisms. Similarly to telmisartan, physical exercises stabilize ΑΤΗ lesion. Moreover results shown that, submitted exercise and telmisartan have an comparable mechanism. In fact, they significantly decrease pro-inflammatory cytokines expression and in the same time activated PPAR-γ expression in arterial wall. Contrary to submitted exercise, voluntary exercises increases expression of anti-inflammatory cytokines IL-1ra and increase M2 marker CD206. These results suggest that voluntary and submitted exercise have two different mechanism of action. Moreover, M2 surexpression in response to voluntary exercise shift the inflammatory balance in favor to M2. Further, this change of balance in favor to M2, is significantly correlated to decrease of ΑΤΗ progression. Voluntary exercises significantly decreases ΑΤΗ progression in the same levels like telmisartan treatment. Voluntary and submitted exercise has two different mechanisms, submitted exercise decrease proinflammatory cytokines expression whereas voluntary exercise increase anti-inflammatory cytokines expression and promote an anti-inflammatory phenotype of macrophages M2. The shift of M1/M2 balance towards M2 decreases atherosclerosis progression.

The role of peroxisome proliferator-activated receptors in the development and physiology of gametes and preimplantation embryos.

In several species, a family of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) composed of three isotypes, is expressed in somatic cells and germ cells of the ovary as well as the testis. Invalidation of these receptors in mice or stimulation of these receptors in vivo or in vitro showed that each receptor has physiological roles in the gamete maturation or the embryo development. In addition, synthetic PPAR gamma ligands are recently used to induce ovulation in women with polycystic ovary disease. These results reveal the positive actions of PPAR in reproduction. On the other hand, xenobiotics molecules (in herbicides, plasticizers, or components of personal care products), capable of activating PPAR, may disrupt normal PPAR functions in the ovary or the testis and have consequences on the quality of the gametes and the embryos. Despite the recent data obtained on the biological actions of PPARs in reproduction, relatively little is known about PPARs in gametes and embryos. This review summarizes the current knowledge on the expression and the function of PPARs as well as their partners, retinoid X receptors (RXRs), in germ cells and preimplantation embryos. The effects of natural and synthetic PPAR ligands will also be discussed from the perspectives of reproductive toxicology and assisted reproductive technology.

Multimeric complexes of the PML-retinoic acid receptor alpha fusion protein in acute promyelocytic leukemia cells and interference with retinoid and peroxisome-proliferator signaling pathways.

The t(15;17) chromosomal translocation, specific for acute promyelocytic leukemia (APL), fuses the PML gene to the retinoic acid receptor alpha (RAR alpha) gene, resulting in expression of a PML-RAR alpha hybrid protein. In this report, we analyzed the nature of PML-RAR alpha-containing complexes in nuclear protein extracts of t(15;17)-positive cells. We show that endogenous PML-RAR alpha can bind to DNA as a homodimer, in contrast to RAR alpha that requires the retinoid X receptor (RXR) dimerization partner. In addition, these cells contain oligomeric complexes of PML-RAR alpha and endogenous RXR. Treatment with retinoic acid results in a decrease of PML-RAR alpha protein levels and, as a consequence, of DNA binding by the different complexes. Using responsive elements from various hormone signaling pathways, we show that PML-RAR alpha homodimers have altered DNA-binding characteristics when compared to RAR alpha-RXR alpha heterodimers. In transfected Drosophila SL-3 cells that are devoid of endogenous retinoid receptors PML-RAR alpha inhibits transactivation by RAR alpha-RXR alpha heterodimers in a dominant fashion. In addition, we show that both normal retinoid receptors and the PML-RAR alpha hybrid bind and activate the peroxisome proliferator-activated receptor responsive element from the Acyl-CoA oxidase gene, indicating that retinoids and peroxisome proliferator receptors may share common target genes. These properties of PML-RAR alpha may contribute to the transformed phenotype of APL cells.

Fatty acids and eicosanoids regulate gene expression through direct interactions with peroxisome proliferator-activated receptors alpha and gamma.

Peroxisome proliferator-activated receptors (PPARs) alpha and gamma are key regulators of lipid homeostasis and are activated by a structurally diverse group of compounds including fatty acids, eicosanoids, and hypolipidemic drugs such as fibrates and thiazolidinediones. While thiazolidinediones and 15-deoxy-Delta12, 14-prostaglandin J2 have been shown to bind to PPARgamma, it has remained unclear whether other activators mediate their effects through direct interactions with the PPARs or via indirect mechanisms. Here, we describe a novel fibrate, designated GW2331, that is a high-affinity ligand for both PPARalpha and PPARgamma. Using GW2331 as a radioligand in competition binding assays, we show that certain mono- and polyunsaturated fatty acids bind directly to PPARalpha and PPARgamma at physiological concentrations, and that the eicosanoids 8(S)-hydroxyeicosatetraenoic acid and 15-deoxy-Delta12,14-prostaglandin J2 can function as subtype-selective ligands for PPARalpha and PPARgamma, respectively. These data provide evidence that PPARs serve as physiological sensors of lipid levels and suggest a molecular mechanism whereby dietary fatty acids can modulate lipid homeostasis.

Peroxisome proliferator-activated receptors: insight into multiple cellular functions.

Peroxisome proliferator-activated receptors, PPARs, (NR1C) are nuclear hormone receptors implicated in energy homeostasis. Upon activation, these ligand-inducible transcription factors stimulate gene expression by binding to the promoter of target genes. The different structural domains of PPARs are presented in terms of activation mechanisms, namely ligand binding, phosphorylation, and cofactor interaction. The specificity of ligands, such as fatty acids, eicosanoids, fibrates and thiazolidinediones (TZD), is described for each of the three PPAR isotypes, alpha (NR1C1), beta (NR1C2) and gamma (NR1C3), so as the differential tissue distribution of these isotypes. Finally, general and specific functions of the PPAR isotypes are discussed, namely their implication in the control of inflammatory responses, cell proliferation and differentiation, the roles of PPARalpha in fatty acid catabolism and of PPARgamma in adipogenesis.

Les récepteurs nucléaires PPARs (Peroxisome Proliferator Activated Receptors) : Trois isotypes pour de multiples fonctions.

Les récepteurs nucléaires font partie d'une superfamille de facteurs de transcription qui regroupe en particulier les récepteurs des hormones stéroïdes et thyroïdiennes, de la vitamine D3 et des rétinoïdes [1]. Ces facteurs de transcription sont impliqués dans de nombreuses fonctions cellulaires comme le développement embryonnaire, la différenciation cellulaire et le contrôle du métabolisme. Ce sont des protéines importantes en recherche médicale puisque un grand nombre d'entre elles sont impliquées dans des pathologies telles que le cancer, le diabète ou les syndromes de résistance aux hormones. À ce jour, cette superfamille comprend différents membres, dont l'activité est modulée par la présence de ligands spécifiques. Néanmoins, pour nombre d'entre eux, aucun ligand endogène spécifique n'a encore été identifié. Ceux-là sont appelés récepteurs orphelins. Orphelins lors de leur découverte il y a dix ans, les PPARs (Peroxisome proliferator-activated receptors) ont été particulièrement étudiés depuis, permettant de leur attribuer des ligands et des fonctions qui les placent au coeur de nombreuses régulations métaboliques.