Peroxisome Proliferator-activated Receptor Modulators Research Articles

Physiological and Nutritional Roles of PPAR across Species

Physiological and Nutritional Roles of PPAR across Species

Peroxisome proliferator-activated receptor targets for the treatment of metabolic diseases.

Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-α and PPAR-γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis.

Design and Synthesis of Dual Modulators of Soluble Epoxide Hydrolase and Peroxisome Proliferator-Activated Receptors

Metabolic syndrome is a complex condition which often requires the use of multiple medications as a treatment. The resulting problems of polypharmacy are increase in side effects, drug-drug interactions, and its high economic cost. Development of multitarget compounds is a promising strategy to avoid the complications arising from administration of multiple drugs. Modulators of peroxisome proliferator-activated receptors (PPARs) are established agents in the treatment of dyslipidaemia, hyperglycaemia, and insulin resistance. Inhibitors of soluble epoxide hydrolase (sEH) are under evaluation for their use in cardiovascular diseases. In the present study, a series of dual sEH/PPAR modulators containing a pyrrole acidic headgroup and a urea pharmacophore were designed, synthesized, and evaluated in vitro using recombinant enzyme and cell-based assays. Compounds with different activity profiles were obtained which could be used in the treatment of metabolic syndrome.

Anti-Diabetic Compounds and their Patent Information: An Update

The increasing epidemic of diabetes mellitus around the globe is increasing the risk of various other chronic diseases i.e. coronary artery diseases, myocardial infarction, hypertension, dyslipidemia and number of other complicated disorders. Diabetes mellitus is clinically characterized by a marked increase in blood glucose levels and is associated with mild hyperlipidemia. Although the prevalence of this health ailment is increasing dramatically, various therapeutic compounds have been developed to treat this disease that is available in the market as synthetic, formulated and combined forms. Recently, various compounds have come through preclinical studies and shown the therapeutic efficacy of using multiple/ specific drug targets. Recent research approaches have been based on receptors targeting, islet cell transplantation, gene expression profiling, glucagon-like peptide-1, dipeptidyl peptidase IV inhibitors, insulin therapy, modulators of peroxisome proliferator-activated receptors (PPAR), glucagon receptor antagonists, insulin analogues, sensitizers and combination therapies. Furthermore various, latest findings claimed to identifying new anti-diabetic regimens with novel mechanism of action are being developed. This review provides an update on the use of approaches to the development of preventive and therapeutic strategies against diabetes and recent patents that could develop into novel therapeutics available to the clinical success for the management of the disease.

Isorhamnetin Inhibits Proliferation and Invasion and Induces Apoptosis through the Modulation of Peroxisome Proliferator-activated Receptor γ Activation Pathway in Gastric Cancer

Gastric cancer (GC) is a lethal malignancy and the second most common cause of cancer-related deaths. Although treatment options such as chemotherapy, radiotherapy, and surgery have led to a decline in the mortality rate due to GC, chemoresistance remains as one of the major causes for poor prognosis and high recurrence rate. In this study, we investigated the potential effects of isorhamnetin (IH), a 3'-O-methylated metabolite of quercetin on the peroxisome proliferator-activated receptor γ (PPAR-γ) signaling cascade using proteomics technology platform, GC cell lines, and xenograft mice model. We observed that IH exerted a strong antiproliferative effect and increased cytotoxicity in combination with chemotherapeutic drugs. IH also inhibited the migratory/invasive properties of GC cells, which could be reversed in the presence of PPAR-γ inhibitor. We found that IH increased PPAR-γ activity and modulated the expression of PPAR-γ regulated genes in GC cells. Also, the increase in PPAR-γ activity was reversed in the presence of PPAR-γ-specific inhibitor and a mutated PPAR-γ dominant negative plasmid, supporting our hypothesis that IH can act as a ligand of PPAR-γ. Using molecular docking analysis, we demonstrate that IH formed interactions with seven polar residues and six nonpolar residues within the ligand-binding pocket of PPAR-γ that are reported to be critical for its activity and could competitively bind to PPAR-γ. IH significantly increased the expression of PPAR-γ in tumor tissues obtained from xenograft model of GC. Overall, our findings clearly indicate that antitumor effects of IH may be mediated through modulation of the PPAR-γ activation pathway in GC.

Abstract 433: Overexpression of Catalase Negates the Beneficial Effects of Dietary Lipids on Plasma Triglycerides and APOA1/C3/A5 Levels

Linoleic acid (LA) and oxidized linoleic acid (OxLA) are major components of Western diet. Both these lipids exert their actions through induction of oxidative stress. Our earlier studies have shown that feeding these dietary lipids to C57Bl/6 mice for two weeks decreased plasma triglyceride levels and up-regulated ApoA5 levels. We hypothesized that decreasing oxidative stress by overexpressing antioxidant Catalase in mice will block these beneficial effects. Methods: 24 male C57Bl/6 mice and 17 male Catalase (CAT) transgenic mice (8-12 weeks old) were divided into three groups each. Each group were fed orally either vehicle alone (ethanol), LA or OxLA (18mg/day) for 2 weeks. At the end of two weeks, the mice were sacrificed and plasma lipid profile along with liver mRNA and protein levels of Catalase and APOA1/C3/A5 was analyzed. Results: LA and OxLA feeding significantly decreased plasma triglycerides in C57Bl/6 mice but not other lipid cholesterols. However, no such changes were observed upon LA or OxLA feeding in CAT mice. The CAT mice expressed significantly higher mRNA levels of liver catalase but decreased APOA1/C3/A5 expression compared to C57Bl/6 mice, which was unaltered by LA or OxLA feeding. These effects were mediated by the modulation of the transcription factor, peroxisome proliferator-activated receptors (PPARs). Conclusion: In conclusion, overexpression of an antioxidant enzyme, catalase negated the beneficial effect of dietary lipids on triglyceride levels by altering the APOA1/C3/A5 pathway through modulation of PPARs. Our results suggest that a minimal level of oxidative stress is beneficial.

Medicinal Chemistry and Actions of Dual and Pan PPAR Modulators

Peroxisome proliferator-activated receptor (PPAR) agonists are used as adjunct therapy in the treatment of diabetes mellitus. Fibrates, including fenofibrate, gemfibrozil, benzafibrate, ciprofibrate, and clofibrate act on PPAR alpha to reduce the level of hypertriglyceridemia. However, agonists (ligands) of PPAR-beta/delta receptors, such as tesaglitazar, muraglitazar, ragaglitazar, imiglitazar, aleglitazar, alter the body's energy substrate preference from glucose to lipids and hence contribute to the reduction of blood glucose level. Glitazones or thiazolidinediones on the other hand, bind to PPAR-gamma receptors located in the nuclei of cells. Activation of PPAR-gamma receptors leads to a decrease in insulin resistance and modification of adipocyte metabolism. They reduce hyperlipidaemia by increasing the level of ATP-binding cassette A1, which modifies extra-hepatic cholesterol into HDL. Dual or pan PPAR ligands stimulate two or more isoforms of PPAR and thereby reduce insulin resistance and prevent short- and long-term complications of diabetes including micro-and macroangiopathy and atherosclerosis, which are caused by deposition of cholesterol. This review examines the chemical structure, actions, side effects and future prospects of dual and pan PPAR agonists.

Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria?

Protein and lipid oxidation-mainly by mitochondrial reactive oxygen species (mtROS)-was proposed as a crucial determinant of health and lifespan. Angiotensin II (Ang II) enhances ROS production by activating NAD(P)H oxidase and uncoupling endothelial nitric oxide synthase (NOS). Ang II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS blockade) increases survival and prevents age-associated changes. RAS blockade reduces mtROS and enhances mitochondrial content and function. This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction. Since Ang II is a pleiotropic peptide, the age-protecting effects of RAS blockade are expected to involve a variety of other mechanisms. Caloric restriction (CR)-an age-retarding intervention in humans and animals-and RAS blockade display a number of converging effects, i.e. they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and insulin-like growth factor-1; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production; and increase uncoupling protein-2 and sirtuin expression. A number of these overlapping effects involve changes in mitochondrial function. In CR, peroxisome proliferator-activated receptors (PPARs) seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition up-regulates PPARs; therefore, it is feasible that PPAR modulation is pivotal for mitochondrial protection by RAS blockade during rodent ageing. Other potential mechanisms that may underlie RAS blockade's mitochondrial benefits are TGF-β down-regulation and up-regulation of Klotho and sirtuins. In conclusion, the available data suggest that RAS blockade deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.

Healing fats of the skin: the structural and immunologic roles of the ω-6 and ω-3 fatty acids

Linoleic acid (18:2ω6) and α-linolenic acid (18:3ω3) represent the parent fats of the two main classes of polyunsaturated fatty acids: the ω-6 (n-6) and the ω-3 (n-3) fatty acids, respectively. Linoleic acid and α-linolenic acid both give rise to other long-chain fatty acid derivatives, including γ-linolenic acid and arachidonic acid (ω-6 fatty acids) and docosahexaenoic acid and eicosapentaenoic acid (ω-3 fatty acids). These fatty acids are showing promise as safe adjunctive treatments for many skin disorders, including atopic dermatitis, psoriasis, acne vulgaris, systemic lupus erythematosus, nonmelanoma skin cancer, and melanoma. Their roles are diverse and include maintenance of the stratum corneum permeability barrier, maturation and differentiation of the stratum corneum, formation and secretion of lamellar bodies, inhibition of proinflammatory eicosanoids, elevation of the sunburn threshold, inhibition of proinflammatory cytokines (tumor necrosis factor-α, interferon-γ, and interleukin-12), inhibition of lipoxygenase, promotion of wound healing, and promotion of apoptosis in malignant cells, including melanoma. They fulfill these functions independently and through the modulation of peroxisome proliferator-activated receptors and Toll-like receptors.

PPAR Modulation of Kinase-Linked Receptor Signaling in Physiology and Disease

Kinase-linked receptors and nuclear receptors connect external cues to gene transcription. Among nuclear receptors, peroxisome proliferator-activated receptors (PPARs) are of special interest in relation to widespread human diseases. Mapping out connections between PPARs and kinase-linked receptor signaling is central to better understand physiological and pathophysiological processes and to better define therapeutic strategies. This is the aim of the present review.

Nuclear Receptors of the Peroxisome Proliferator-Activated Receptor (PPAR) Family in Gestational Diabetes: From Animal Models to Clinical Trials1

Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance and affects 2%-8% of all pregnancies. Among other complications, GDM can lead to the development of type 2 diabetes mellitus (DM 2) in both mother and child. Peroxisome proliferator-activated receptors (PPARs) are major regulators of glucose and lipid metabolism. Furthermore, PPARs are mediators of inflammation and angiogenesis and are involved in the maternal adaptational dynamics during pregnancy to serve the requirements of the growing fetus. PPARs were originally named for their ability to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. The expression of three PPAR isoforms, alpha, beta/delta, and gamma, have been described. Each of them is encoded by different genes; however, they share 60%-80% homology in their ligand-binding and DNA-binding domains. PPARs are involved in trophoblast differentiation, invasion, metabolism, and parturition and are expressed in invasive extravillous trophoblast and villous trophoblast cells. Nuclear receptors, to which PPARs belong, are promising targets for disease-specific treatment strategies because they act as transcription factors controlling cellular processes at the level of gene expression and may produce selective alterations in downstream gene expression. To date, PPAR agonists are therapeutically used in patients with DM 2 and in patients with reproductive disorders such as polycystic ovary syndrome. Because of safety concerns and limited data, PPAR agonists are not yet included in GDM-related treatment strategies. Our objective herein is to review newly emerging generations of selective PPAR modulators and panagonists, which may have potent therapeutic implications in the context of GDM.

Changing the binding mode to peroxisome proliferator activated receptor (PPAR) alpha/gamma: a new ligand with improved antidiabetic and antiobesity properties

PPARs are ligand activated transcription factors playing a key role in lipid, glucose and energy metabolism. PPAR agonists are used as hypolipidemic and antidiabetic agents, however since these ligands have shown side effects, the hunt for selective PPAR modulators avoiding adverse reactions is still open.By a transfection based screening we identified LT175 that binds and activates both PPARα and γ subtypes. The 3D structures of PPARγ/LT175 complex reveals a new binding mode with a distinct coactivator recruitment profile. In transcription assays with PPRE‐Luc reporter mice, LT175 activates PPAR program in target tissues. In high fat fed mice, LT175 ameliorates the metabolic profile and reduces visceral adiposity. Circulating levels of adiponectin increases while plasma insulin decreases. LT175 enhances the expression of target genes in the liver and adipose tissue. We also observed increased brown fat mass that contributes to decrease body weight via fat burning an effect secondary to an increased FGF‐21 expression. Altogether, we demonstrate that LT175 is a lead compound with favorable effects on glucose and lipid metabolism that could be developed to treat diabetes and obesityFunded by FP6 LSHM‐CT‐2006‐037498 from the European Community to MC and The Giovanni Armenise‐Harvard Foundation career development grant to NM

The rise and fall of rosiglitazone

This editorial refers to ‘Heart failure events with rosiglitazone in type 2 diabetes: data from the RECORD clinical trial’[†][1], by M. Komajda et al. on page 824 Komajda et al. have described the increased incidence of congestive heart failure (CHF) in patients treated with rosiglitazone in the RECORD Trial (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes).1 This study is the latest chapter in the tortured saga of rosiglitazone, a drug that was once the largest selling diabetes therapy in the world.2 The rise and fall of rosiglitazone raises critical scientific and ethical questions about drug development and marketing, with profound consequences, including the recent decision by US regulatory authorities to require cardiovascular outcome studies for all new diabetes drugs.3 Rosiglitazone and related thiazolidindiones (TZDs) are modulators of nuclear receptor proteins known as peroxisome proliferator-activated receptors (PPARs) that function as transcription factors regulating expression of genes. Of the many subclasses of PPAR modulators, two types have been marketed, PPARα agents, such as fenofibrate, that affect lipid metabolism, and PPARγ agents, such as rosiglitazone, that act as insulin sensitizers. One marketed TZD, pioglitazone, is considered a dual PPAR agonist, with modest α effects and strong γ effects. PPARs influence a large number of genes, perhaps 100 or more, most of which have unknown biological effects. Accordingly, the effects of these agents are unpredictable and can result in unusual toxicities. Indeed, during the past decade, >50 PPAR agonists have failed during clinical development, some due to cardiotoxicity,4 although few publications have detailed the precise toxicity encountered. One agent, muraglitazar, was recommended for approval by a US Food and Drug Administration (FDA) advisory panel, but ultimately not approved after a meta-analysis of clinical trials obtained from FDA documents revealed an approximate doubling of adverse cardiovascular outcomes. … *Corresponding author: Tel: +1 216 445 6852, Fax: +1 216 445 6855, Email: Nissens{at}ccf.org [1]: #fn-2

Phytochemicals as Modulators of PPARs and RXRs

Welcome to this special issue of PPAR Research on “Phytochemicals as modulators of PPARs and RXRs.” Plants have played a crucial role in the prevention and treatment of human diseases for thousands of years. A significant number of contemporary drugs with high efficacy are derived from herbal origin. These natural phytochemicals, including certain nutrients, are therefore of great medicinal value. Peroxisome proliferator-activated receptors (PPARs) belong to the steroid hormone receptor superfamily that bind to and are activated by fatty acids, eicosanoids, and a group of xenobiotics called peroxisome proliferators. Each of these receptors binds to specific peroxisome proliferator response elements (PPRE) as a heterodimer with a retinoid X receptor (RXR). Binding to these receptors has been proven to control the pathological conditions associated with obesity, aging-related diseases, inflammation, immune disorder, cell cycle regulation as well as cancer. There is a strong mechanistic basis for PPAR and RXR targeting, as these nuclear receptors are transcriptional factors that modulate gene expression relevant to the control of blood glucose and lipids, as well as the processes of inflammation and carcinogenesis. Since PPARs play an important role in lipid metabolism, the search for natural ligands had begun with fatty acids and eicosanoids. In fact, the discovery that many natural dietary compounds, especially phytochemicals, are PPAR activators is of great significance for human health. With metabolic syndrome, diabetes, and chronic systemic inflammatory diseases now reaching pandemic proportions, the importance of the discovery of natural PPAR ligands is self-evident. The special issue begins with a review of terpenoids as modulators of the PPAR family. To date more than 40,000 terpenoids have been described. Also known as isoprenoids, terpenoids constitute one of the largest and most diverse group of phytochemicals. Members of this phytochemical family are well known to us as the flavours of cinnamon, ginger, and cloves and the scents of camphor and eucalyptus. The vitamin A precursors known as carotenoids and psychoactive cannabinoids are also forms of terpenoid. In this issue, T. Goto and colleagues review the biosynthesis, metabolism, and plant origins of various dietary terpenoids. The physiological effects of these compounds on carbohydrate and lipid metabolism are described in terms of their PPARγ and PPARα activating abilities. This is followed by the research article on the kinetic assessment and therapeutic modulation of metabolic and obesity-associated inflammatory profiles by a high-fat diet, whereas the whole process was found to be mediated by PPAR activation. Another research article has proposed glycyrrhizic acid, the bioactive compound extracted from roots of licorice (Glycyrrhiza glabra), as a potent PPARγ agonist. This phytochemical is capable of ameliorating metabolic syndrome by affecting glucose homeostasis, lipid metabolism, and adipogenesis. The focus is then shifted to the findings on verbascoside, a phytochemical that exerts a strong anti-inflammatory activity against the development of experimental inflammatory bowel disease. This work by the S. Cuzzocrea team has proven that verbascoside is a PPARα ligand by using a knock-out animal model. S. N. Lewis and colleagues conclude this special issue with a comprehensive review of computational approaches to the discovery of phytochemical ligands for PPARα and PPARγ. This timely review is an excellent reference document for the existing 3D structures of PPAR receptors cocrystallized with a variety of ligands and available on-line at the RCSB database. Lewis gives an expert description of the potential for in silico screening of phytochemical databases. The challenges of applying computational techniques to the analysis of a flexible ligand binding to a flexible receptor are described. This review is a most helpful exposition of the state-of-the-art computational methods regarding natural PPAR ligand discovery. Joshua K. Ko Susanna S. Lee Harry Martin

Various Terpenoids Derived from Herbal and Dietary Plants Function as PPAR Modulators and Regulate Carbohydrate and Lipid Metabolism

Several herbal plants improve medical conditions. Such plants contain many bioactive phytochemicals. Terpenoids (also called “isoprenoids”) constitute one of the largest families of natural products accounting for more than 40,000 individual compounds of both primary and secondary metabolisms. In particular, terpenoids are contained in many herbal plants, and several terpenoids have been shown to be available for pharmaceutical applications, for example, artemisinin and taxol as malaria and cancer medicines, respectively. Various terpenoids are contained in many plants for not only herbal use but also dietary use. In this paper, we describe several bioactive terpenoids contained in herbal or dietary plants, which can modulate the activities of ligand-dependent transcription factors, namely, peroxisome proliferator-activated receptors (PPARs). Because PPARs are dietary lipid sensors that control energy homeostasis, daily eating of these terpenoids might be useful for the management for obesity-induced metabolic disorders, such as type 2 diabetes, hyperlipidemia, insulin resistance, and cardiovascular diseases.

New therapies for diabesity

Many patients with type 2 diabetes are obese (diabesity), and the two conditions together impose a particularly complex therapeutic challenge. Several differently acting agents are often required at the same time, encouraging development of more single-tablet combinations. Longer-acting (once daily and once weekly) injected agonists of glucagon-like peptide-1 are due to provide additional options to stimulate insulin secretion with weight loss and minimal risk of hypoglycemia. Further, dipeptidyl peptidase-4 inhibitors ("weight-neutral" insulinotropic agents) are also expected. Sodium-glucose cotransporter 2 inhibitors offer a new option to reduce hyperglycemia and facilitate weight loss by increasing the elimination of glucose in the urine. Selective peroxisome proliferator-activated receptor modulators are being studied to produce compounds with desired effects. Many other agents with antidiabetic and antiobesity activity are progressing in clinical development.

Syntheses of a Selective Peroxisome Proliferator Activated Receptor Modulator and Practical New Preparations of 2-(4-Alkoxyphenyl)ethylamines

This article describes chemistry that was developed to give access to multigram quantities of the selective peroxisome proliferator activated receptor modulator (SPPARM), compound 1.1 Fischer esterifications, phase transfer-catalyzed alkylations, amide couplings, crystallizations, and a new synthesis were developed to accomplish this task. In addition, an efficient method for preparing 2-(4-alkoxyphenyl)ethylamines 7a−d from tyramine 9 was developed that involves O-alkylation of intermediate Schiff base 11 and subsequent acid-catalyzed hydrolysis to afford the target molecules as crystalline hydrochloride salts.

Metabolic effects of various antidiabetic and hypolipidaemic agents on a high-fat diet and multiple low-dose streptozocin (MLDS) mouse model of diabetes

Insulin resistance and subsequent insulin secretory defect are two main features of type 2 diabetes and associated metabolic disorders. The animal models of type 2 diabetes are very complex and are as heterogeneous as the disease. We have evaluated the effect of various antidiabetic and lipid lowering agents (fenofibrate, rosiglitazone, glimepiride, metformin and simvastatin) on the metabolic abnormalities induced by combining a high-fat diet and multiple low-dose streptozocin (MLDS) in mice. Male Swiss albino mice were orally treated with the above agents and fed with a diet containing high fat for 28 days. On day 15 the animals were injected intraperitoneally with low-dose streptozocin (40 mg kg(-1)), which was administered for five consecutive days. At the end of the 28-day treatment plasma metabolic parameters (glucose, triglyceride and immunoreactive insulin) were estimated. The antidiabetic and hypolipidaemic agents exhibited differential effects on these metabolic parameters. With the exception of fenofibrate all these agents reduced the plasma glucose levels, and the effects of metformin and rosiglitazone on glucose were found to be statistically significant. Although the effect of the test drugs on cholesterol was modest, a significant decrease in triglyceride levels was observed with sub-chronic treatment with these agents. Interestingly, glimepiride mildly elevated the insulin levels while the other antidiabetics and hypolipidaemics reduced the insulin levels, with metformin and rosiglitazone exhibiting statistically significant effects on insulin. To our knowledge this is the first report on the effect of various peroxisome proliferator-activated receptor modulators and newer antidiabetics on the metabolic effects induced by the combined high-fat diet and MLDS model of type 2 diabetes in Swiss albino mice. The results suggested the complexity of the hyperglycaemia, hyperinsulinaemia and hypertriglyceridaemia induced by the high-fat diet and MLDS mouse model, and their correction by various antidiabetics and antihyperlipidaemics may have involved diverse mechanisms.

Endothelial Progenitor Cells and Angiogenesis Join the PPARty

See related article, pages 80–88 Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily.1 In mammals, the PPAR family consists of 3 subtypes of proteins encoded by separate genes: PPARα (NR1C1), PPARγ (NR1C3), and PPARδ (also known as β or NR1C2).2 They act as heterodimers with the retinoid X receptor and regulate gene transcription by binding to specific response elements in the promoter of the target genes.3 The classical biological activity of PPARα is the regulation of the rate of fatty acid uptake and their esterification into triglyceride or oxidation,4–7 whereas PPARγ is classically involved in adipocyte differentiation, regulation of fat storage, and maintenance of glucose homeostasis.5 The physiological functions of PPARδ are instead still unclear, although it is known that this receptor contributes to an inflammatory switch through its association and disassociation with transcriptional repressors.8 The clinical importance of PPARs originates with fibrates and thiazolidinediones (TZDs), which respectively act on PPARα and PPARγ and are used to ameliorate hyperlipidemia and hyperglycemia in subjects with type 2 diabetes mellitus (T2DM). Fibrates, such as gemfibrozil, clofibrate, fenofibrate, and bezofibrate, are drugs that effectively reduce triglycerides (TG) and free …

Confusion over thiazolidinedione-induced heart failure: need for a better definition of heart failure

Evaluation of: Erdmann E, Wilcox RG. Weighing up the cardiovascular benefits of thiazolidinedione therapy: the impact of increased risk of heart failure. Eur. Heart J. 29(1), 12–20 (2008).Thiazolidinediones (TZDs) reduce insulin resistance through the modulation of peroxisome proliferator-activated receptor (PPAR)-γ activity and are, therefore, used for the treatment of individuals with Type 2 diabetes. TZDs have been blamed for inducing heart failure (HF) and are contraindicated in patients with impaired ventricular function. Whether precipitation of HF by TZDs is overestimated or not remains hotly debated in the scientific community. One message from the TZD–HF debacle is that current definitions of HF lack scientific rigour as they fail to assess cardiac organ function directly using a representative and reliable method. Once cardiologists reappraise and update the current definition of HF, appropriate steps can then be taken to answer the question of whether TZDs really induce true HF.