Peroxisome Proliferator-activated Receptor Modulators Research Articles

Peroxisome proliferator-activated receptors: a therapeutic target in COPD?: Fig. 1—

Extrapulmonary pathology significantly impairs clinical outcome in chronic obstructive pulmonary disease (COPD). The peroxisome proliferator-activated receptors (PPARs) are implicated in the regulation of several hallmarks of systemic COPD pathology, including cachexia, decreased oxidative muscle metabolism, oxidative stress and systemic inflammation. Recently, expression of PPARs and related cofactors was shown to be reduced in peripheral skeletal muscle of patients with moderate-to-severe COPD and muscle weakness. The current authors hypothesise that impaired peroxisome proliferator-activated receptor signalling may underlie some of the muscular disturbances in chronic obstructive pulmonary disease. Proposed mechanisms will be outlined in the present article, as well as the therapeutic potential of peroxisome proliferator-activated receptor modulation in the treatment of skeletal muscle dysfunction.

PPARs and the kidney in metabolic syndrome

The metabolic syndrome (MetS) is defined by a set of metabolic risk factors, including insulin resistance, central obesity, dyslipidemia, hyperglycemia, and hypertension for type 2 diabetes and cardiovascular disease. Although both retrospective and prospective clinical studies have revealed that MetS is associated with chronic renal disease, even with a nondiabetic cause, the cellular and molecular mechanisms in this association remain largely uncharacterized. Recently, increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs), a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors, may play an important role in the pathogenesis of MetS. All three members of the PPAR nuclear receptor subfamily, PPARalpha, -beta/delta, and -gamma, are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, inflammation, and blood pressure. PPARs have also been implicated in many renal pathophysiological conditions, including diabetic nephropathy and glomerulosclerosis. Ligands for PPARs such as hypolipidemic PPARalpha activators, and antidiabetic thiazolidinedione PPARgamma agonists affect not only diverse aspects of MetS but also renal disease progression. Emerging data suggest that PPARs may be potential therapeutic targets for MetS and its related renal complications. This review focuses on current knowledge of the role of PPARs in MetS and discusses the potential therapeutic utility of PPAR modulators in the treatment of kidney diseases associated with MetS.

PPARδ Agonism for the Treatment of Obesity and Associated Disorders: Challenges and Opportunities

The prevalence of obesity in the USA and worldwide has reached epidemic proportions during the last two decades. Drugs currently available for the treatment of obesity provide no more than 5% placebo-adjusted weight loss and are associated with undesirable side effects. Peroxisome proliferator-activated receptor (PPAR) modulators offer potential benefits for the treatment of obesity and its associated complications but their development has been complicated by biological, technical, and regulatory challenges. Despite significant challenges, PPAR modulators are attractive targets for the treatment of obesity and could offer a viable alternative to the millions of patients who fail to lose weight following rigorous dieting and exercise protocols. In addition, PPAR modulators have the potential-added benefit of ameliorating the associated comorbidities.

From Dual Peroxisome Proliferator Activated Receptor Agonists to Selective Peroxisome Proliferator Activated Receptor Modulators

Worldwide epidemic of type 2 diabetes mellitus, obesity, dyslipidemia, hypertension and atherosclerosis (i.e. metabolic syndrome) still requires further treatment strategies. Life style change can be regarded as single evidenced option to manage these co-morbid conditions, at the same time. Peroxisome proliferator activated receptors (PPARs) are claimed to play critical roles in metabolic adaptation to changing environmental factors. PPAR alpha and gamma agonists are approved as hypolipidemic and antidiabetic agents, respectively. Combination of PPAR alpha and gamma agonistic effects in a single molecule (i.e. dual PPAR agonists) has been tried to achieve a better multiple cardiovascular risk management. Despite their efficacy, dual PPAR agonists has been discontinued due to safety concerns. New generation of PPAR ligands with a higher safety profile is being actively investigated. Here, we review pursuits for a new PPAR class, and discuss the potential role for selective peroxisome proliferator activated receptor modulators (SPPARMs) as new patented molecules. This article also includes recent patents on this topic. Keywords: Peroxisome proliferator activated receptors, dual PPAR agonists, SPPARMs, type 2 diabetes, metabolic syndrome, atherosclerosis, GW0072, FK614, AMG131, nTZDpa

Peroxisome Proliferators‐Activated Receptor (PPAR) Modulators and Metabolic Disorders

Overweight and obesity lead to an increased risk for metabolic disorders such as impaired glucose regulation/insulin resistance, dyslipidemia, and hypertension. Several molecular drug targets with potential to prevent or treat metabolic disorders have been revealed. Interestingly, the activation of peroxisome proliferator-activated receptor (PPAR), which belongs to the nuclear receptor superfamily, has many beneficial clinical effects. PPAR directly modulates gene expression by binding to a specific ligand. All PPAR subtypes (α, γ, and σ) are involved in glucose metabolism, lipid metabolism, and energy balance. PPAR agonists play an important role in therapeutic aspects of metabolic disorders. However, undesired effects of the existing PPAR agonists have been reported. A great deal of recent research has focused on the discovery of new PPAR modulators with more beneficial effects and more safety without producing undesired side effects. Herein, we briefly review the roles of PPAR in metabolic disorders, the effects of PPAR modulators in metabolic disorders, and the technologies with which to discover new PPAR modulators.

Peroxisome Proliferator‐Activated Receptors and Progression of Colorectal Cancer

The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. These receptors are also ligand-dependent transcription factors responsible for the regulation of cellular events that range from glucose and lipid homeostases to cell differentiation and apoptosis. The importance of these receptors in lipid homeostasis and energy balance is well established. In addition to these metabolic and anti-inflammatory properties, emerging evidence indicates that PPARs can function as either tumor suppressors or accelerators, suggesting that these receptors are potential candidates as drug targets for cancer prevention and treatment. However, conflicting results have emerged regarding the role of PPARs on colon carcinogenesis. Therefore, further investigation is warranted prior to considering modulation of PPARs as an efficacious therapy for colorectal cancer chemoprevention and treatment.

The Molecular Mechanisms Underlying the Proinflammatory Actions of Thiazolidinediones in Human Macrophages

It is hypothesized that the antiinflammatory actions of peroxisome proliferator-activated receptors (PPARs) may explain the protective effect of these receptors in diabetes, atherosclerosis, cancer, and other inflammatory diseases. However, emerging evidence for proinflammatory activities of activated PPARs is concerning in light of new studies that associate PPAR modulators with an increased incidence of both cardiovascular events in humans and the sporadic formation of tumors in rodents. In an attempt to define the role of each PPAR subtype in inflammation, we made the unexpected observation that human PPARdelta is a positive regulator of inflammatory responses in both monocytes and macrophages. Notably, TNFalpha-stimulated cells administered PPARdelta agonists express and secrete elevated levels of inflammatory cytokines. Most surprising, however, was the finding that thiazolidinediones (TZDs) and other known PPARgamma ligands display different degrees of proinflammatory activities in a PPARgamma- and PPARalpha-independent manner via their ability to augment PPARdelta signaling. A series of mechanistic studies revealed that TZDs, at clinically relevant concentrations, bind and activate the transcriptional activity of PPARdelta. Collectively, these studies suggest that the observed proinflammatory and potentially deleterious effects of PPARgamma ligands may be mediated through an off-target effect on PPARdelta. These studies highlight the need for PPAR modulators with increased receptor subtype specificity. Furthermore, they suggest that differences in systemic exposure and consequently in the activation of PPARgamma and PPARdelta may explain why TZDs can exhibit both inflammatory and antiinflammatory activities in humans.

The Endocrine Disruptor Monoethyl-hexyl-phthalate Is a Selective Peroxisome Proliferator-activated Receptor γ Modulator That Promotes Adipogenesis

The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.

A new guest playing with bone and fat

it is now known that some hormones are produced by different organs, and they can act through a number of pathways, including membrane and nuclear receptors. Furthermore, a series of hormone metabolites, previously considered inactive compounds, are physiologically relevant. These features are also

Peroxisome Proliferator–Activated Receptors as Transcriptional Nodal Points and Therapeutic Targets

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (alpha, gamma, and delta, also known as beta or beta/delta) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPARalpha, and thiazolidinediones, which activate PPARgamma, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.

Asymmetric Cleavage of β-Carotene Yields a Transcriptional Repressor of Retinoid X Receptor and Peroxisome Proliferator-Activated Receptor Responses

beta-Carotene and its metabolites exert a broad range of effects, in part by regulating transcriptional responses through specific nuclear receptor activation. Symmetric cleavage of beta-carotene can yield 9-cis retinoic acid (9-cisRA), the natural ligand for the nuclear receptor RXR, the obligate heterodimeric partner for numerous nuclear receptor family members. A significant portion of beta-carotene can also undergo asymmetric cleavage to yield apocarotenals, a series of poorly understood naturally occurring molecules whose biologic role, including their transcriptional effects, remains essentially unknown. We show here that beta-apo-14'-carotenal (apo14), but not other structurally related apocarotenals, represses peroxisome proliferator-activated receptors (PPAR) and RXR activation and biologic responses induced by their respective agonists both in vitro and in vivo. During adipocyte differentiation, apo14 inhibited PPARgamma target gene expression and adipogenesis, even in the presence of the potent PPARgamma agonist BRL49653. Apo14 also suppressed known PPARalpha responses, including target gene expression and its known antiinflammatory effects, but not if PPARalpha agonist stimulation occurred before apo14 exposure and not in PPARalpha-deficient cells or mice. Other apocarotenals tested had none of these effects. These data extend current views of beta-carotene metabolism to include specific apocarotenals as possible biologically active mediators and identify apo14 as a possible template for designing PPAR and RXR modulators and better understanding modulation of nuclear receptor activation. These results also suggest a novel model of molecular endocrinology in which metabolism of a parent compound, beta-carotene, may alternatively activate (9-cisRA) or inhibit (apo14) specific nuclear receptor responses.

Today's challenges and tomorrow's opportunities: ligands to peroxisome proliferator‐activated receptors as therapies for type 2 diabetes and the metabolic syndrome

AbstractFor over a decade, scientists have been investigating the sub‐family of nuclear hormone receptors known as the peroxisome proliferator‐activated receptors (PPARs) as potential targets for improved therapies for type 2 diabetes (T2D). Initial efforts focused on compounds with the thiazolidinedione (TZD) structure, synthesizing compounds based on structural differences followed by testing in rodent models without knowing the molecular target. Once the receptor for the TZDs was identified as PPARγ, more extensive efforts began to identify and develop improved versions of the TZDs. Many biotechnology and pharmaceutical companies using this information established assays that were used in high through‐put screening efforts to identify compounds with greater affinity and selectivity to the receptor. Surprising, these extensive efforts have not led to improved therapies but, in fact, have identified molecules with improved efficacy but with more severe and diverse liabilities. Today, scientists continue to pursue the PPAR subfamily as a target for advanced treatments for T2D and the metabolic syndrome. New approaches include selective PPAR modulators, expansion into the PPARα and PPARδ subtypes, and partial agonists with dual or pan PPAR properties. These drug discovery efforts will continue, as T2D and the associated metabolic diseases become severe medical problems in nations worldwide. Eventually, new and improved therapies will emerge based on the extensive preclinical and clinical knowledge that has accumulated from research and discovery on PPARs by dedicated and thoughtful scientists in search of improved therapies for people with T2D. Drug Dev. Res. 67:574–578, 2006. © 2006 Wiley‐Liss, Inc.

Antipsychotic induced metabolic abnormalities: An interaction study with various PPAR modulators in mice

Abnormalities in glucose and lipid regulation have been reported in schizophrenia during antipsychotic medications. The objectives of the present study were to evaluate the effect of various peroxisome proliferator-activated receptor modulators viz. glimepiride, rosiglitazone and fenofibrate on chlorpromazine, clozapine and ziprasidone induced hyperglycemia and hyperlipidemia in mice. Male Swiss albino mice were orally treated with chlorpromazine, clozapine and ziprasidone concurrently with the antidiabetic medications for 7 days. Plasma glucose, insulin and triglyceride levels were determined at the end of the study. Chlorpromazine and clozapine elevated the glucose and triglyceride levels in normal mice, with no effect on insulin but ziprasidone increased the basal triglyceride and insulin levels and did not have any effect on glucose. Glimepiride and rosiglitazone showed beneficial glucose and triglyceride lowering effects in chlorpromazine and clozapine animals and no effect on insulin levels. Fenofibrate significantly reduced the glucose levels only in animals treated with clozapine, and exhibited significant reduction of triglyceride levels in chlorpromazine, clozapine and ziprasidone treated animals. All three antidiabetic/hypolipidemic agents lowered triglyceride and insulin levels in ziprasidone treated animals. The results of the present studies suggest that hyperglycemia, hyperinsulinemia and hypertriglyceridemia induced by various antipsychotics may involve diverse mechanisms.

Modulation of peroxisome proliferator-activated receptor δ and γ transcripts in swine endometrial tissue during early gestation

Recent evidence points to a role for peroxisome proliferator-activated receptors (PPARs) delta and gamma in embryo implantation and survival. In this study, we report the porcine PPARdelta complete coding sequence and mRNA abundance of PPARdelta, PPARgamma1 and gamma2, angiopoietin-like protein 4 (ANGPTL4) and adipocyte determination and differentiation-dependent factor 1 (ADD1) genes in the pregnant sow endometrium. Real-time PCR analysis was used to study the effect of parity (Yorkshire-Landrace multiparous (YL) and nulliparous (YLn)), site of endometrial tissue sampling (between and at embryo attachment sites) in crossbred DurocxYorkshire-Landrace (DYL) sows and stages of pregnancy (non-pregnant, day 15 and day 25 after mating) in Meishan-Landrace (ML) on mRNA levels. Parity effects were observed for PPARdelta, ANGPTL4, and ADD1, with higher mRNA levels in YL than YLn sows. In DYL sows, lower mRNA levels were present at attachment sites compared to between attachment sites for PPARdelta, PPARgamma1, and ANGPTL4. Finally, day 15 pregnant ML sows had lower PPARdelta mRNA levels compared to day 15 cycling ML sows. A significant increase of PPARgamma1 mRNA levels was found on day 25 pregnant ML and DYL sows relative to day 15 ML or DYL pregnant sows. PPARdelta and gamma immunostaining was detected in endometrial tissue of day 15 cycling sows, day 15 and 25 pregnant sows and epithelial cells of day 25 embryos. Collectively, our results suggest a role for PPARdelta, PPARgamma1, and ANGPTL4, but not PPARgamma2, during the peri-implantation period in pregnant sows.

Fine Tuning of PPAR Ligands for Type 2 Diabetes and Metabolic Syndrome

Type 2 diabetes mellitus (T2DM) is highly prevalent chronic disease. Recently, many biological targets are discovered for treatment of this disease. The identification of the nuclear hormone receptor peroxisome proliferator activated receptors (PPAR) and their subtypes alpha, gamma and delta or beta as targets for controlling lipid, glucose and energy homeostasis has proved to be exciting. As hyperlipidaemia, obesity and insulin resistance are independent risk factors for coronary heart disease and macrovascular complications of diabetes; new agents that increase insulin sensitivity as well as decrease hyperlipidaemia by distinct yet complementary mechanism are being studied as they may provide improved therapy for T2DM and related disorders. In this article, we review highly potent PPARgamma agonists, PPARalpha/gamma dual agonists, PPAR pan agonists, alternative PPAR ligands like partial agonists or selective PPAR modulators (SPPARMs) and antagonists from a chemist point of view.

Selective Modulators of PPAR Activity as New Therapeutic Tools in Metabolic Diseases

Peroxisome Proliferator Activated Receptors (PPARs) are regulators of metabolic pathways mainly of lipid metabolism and energy balance. Their medical importance is given by the fact that they have been implicated in development of insulin resistance, obesity and atherosclerosis. In recent years, major progress has been made in understanding the molecular basis of the function of these receptors. As a result of structural studies and identification of putative natural as well as synthetic ligands and activators of PPARs a new concept emerged and new drugs are on their ways to the clinic. The concept of Selective PPAR Modulators (SPPARM) was suggested by analogy to Selective Estrogen Receptor Modulators (SERM). SPPARMs activate the receptors in distinct ways leading to differential gene expression and biological response. The key features in understanding their action is most likely at the molecular details of ligand binding and the subsequently induced conformational changes as well as cofactor binding. A key aspect of this is that unlike classical steroid hormone receptors such as the retinoic acid receptor, the PPAR receptors have a rather large ligand-binding pocket which is not filled with the ligand entirely and the ligand also stabilizes the receptor's structure. The liganded receptor can have distinct conformations and this leads to different binding affinities for the various cofactors (coactivators and corepressors). In this review, we will introduce this concept, review the literature that supports it and present an overview of the receptor selective ligands including data about their mechanism of action and biological effects.

Molecular Characterization of New Selective Peroxisome Proliferator–Activated Receptor γ Modulators With Angiotensin Receptor Blocking Activity

Selective peroxisome proliferator-activated receptor (PPAR) gamma modulation is a new pharmacological approach that, based on selective receptor-cofactor interactions and target gene regulation, should result in potent insulin sensitization in the absence of PPARgamma-mediated adverse effects. Here, we characterize two angiotensin receptor blockers (ARBs), telmisartan and irbesartan, as new selective PPAR modulators (SPPARMs). Analysis of PPARgamma protein conformation using protease protection showed that telmisartan directly interacts with the receptor, producing a distinct conformational change compared with a glitazone. Glutathione S-transferase pull-down and fluorescence resonance energy transfer assays revealed selective cofactor binding by the ARBs compared with glitazones with an attenuated release of the nuclear receptor corepressor and absence of transcriptional intermediary factor 2 recruitment by ARBs. Consistently, selective cofactor binding resulted in differential gene expression profiles in adipocytes (ARB versus glitazone treated) assessed by oligo microarray analysis. Finally, telmisartan improved insulin sensitivity in diet-induced obese mice in the absence of weight gain. The present study identifies two ARBs as new SPPARMs. SPPARM activity by ARBs could retain the metabolic efficacy of PPARgamma activation with reduction in adverse effects exerting in parallel AT1 receptor blockade. This may provide a new therapeutic option for better cardiovascular risk management in metabolic diseases and may initiate the development of new classes of drugs combining potent antihypertensive and antidiabetic actions.

Modulation of peroxisome proliferator-activated receptors (PPARs) by PPARα- and PPARγ-specific ligands and by 17β-estradiol in isolated zebrafish hepatocytes

Peroxisome proliferation is a phenomenon occurring when responsive animals are exposed to certain compounds so-called peroxisome proliferators and is regulated through a nuclear receptor named peroxisome proliferator-activated receptor (PPAR). PPAR family members exhibit a strong binding affinity for both saturated and unsaturated fatty acids. Activators of PPARα include a variety of endogenously present fatty acids, leukotrienes and hydroxyeicosatetraenoic acids (HETEs) and clinically used drugs, such as fibrates. PPARβ activators include fatty acids, prostaglandin A 2 (PGA 2) and prostacyclin (PGI 2). PPARγ is the most selective receptor and, among others, 15-deoxy-Δ 12,14 prostaglandin J 2 (PGJ 2) has been described to be a PPARγ-specific ligand. The aim of the present study was to determine if known PPARα and PPARγ ligands were able to alter the expression of these subtypes in an in vitro model of zebrafish primary hepatocyte culture. With this purpose, a PPARα specific ligand (8S-HETE), a PPARγ specific ligand (PGJ 2) and a peroxisome proliferator of the fibrate class (clofibrate) were selected. In addition, the female hormone 17β-estradiol was also used as it is known to interact with PPARs. After cell exposure for 24 h, cells were immunohistochemically stained for both PPARs and immunolabeling was quantified as percentage of positive nuclei and cells. Levels of expression of PPARs were also measured by image analysis as grey level per cell. Expression was induced for both PPARα and PPARγ by clofibrate (at 0.5 mM for PPARα and at 1 and 2 mM for PPARγ), by HETE (1 μM), and by PGJ 2 (0.3 and 1 μM for PPARα and 0.3 μM for PPARγ). Expression of PPARγ was also induced at 10 μM by 17β-estradiol. The percentage of PPARα positive nuclei increased significantly at 1 μM HETE and the percentage of PPARγ positive cells decreased at 10 μM 17β-estradiol. As a conclusion, clofibrate, HETE and PGJ 2 are able to induce expression of both PPARα and PPARγ in zebrafish primary hepatocyte cultures. Further studies are needed to identify how the expression of different PPAR subtypes is regulated and to elucidate the implication of PPAR subtypes in zebrafish cell functions.

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferator-activated receptor delta (PPARdelta), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPARdelta. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5'-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPARdelta but not PPARalpha or PPARgamma in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPARdelta activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPARdelta is involved in the signaling pathway.

Peroxisome Proliferator-Activated Receptor Family and Its Relationship to Renal Complications of the Metabolic Syndrome

Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.