Role of PPARs and their isoforms in metabolic disorders related to insulin resistance and diabetes

PPARs play a key role in energy homeostasis, inflammation, development of insulin resistance, and the metabolic syndrome. Therefore, special attention is paid to the synthesis of PPAR ligands (fibrates, thiazolidinediones). Three isoforms of PPARs are activated by fatty acids and their derivatives—eicosanoids. The Pro12Ala polymorphism of the PPARG2 gene is associated with insulin sensitivity of tissues and risks of developing diabetes. It is assumed that PPAR polymorphisms are related to differential responses to pharmacotherapy; this is the basis for the development of personalized medicines and assessments of prognoses.     

过氧化物酶体增殖物激活受体与动脉粥样硬化

过氧化物酶体增殖物激活受体 (peroxisomeproliferator activatedreceptors ,PPARs)是核受体超家族中的一类配体依赖的核转录因子 ,包括α、β/δ和γ三种亚型 ,在脂肪细胞分化、能量代谢和炎症过程中都发挥重要的作用。最近的研究显示 ,PPARs的活化不仅可以改善包括糖尿病、高血压和肥胖等在内的胰岛素抵抗综合征 ,而且还直接作用于血管壁 ,从而减缓动脉粥样硬化的进程。本综述将就PPARs的结构、功能、与动脉粥样硬化发病机制和治疗相关的最新研究进展进行简要介绍。     

PPAR家族及其与代谢综合征的关系

过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)是配体激活的转录因子核受体超家族成员之一。目前已知有三种亚型：PPARα、-β／δ和-γ。它们在脂肪生成、脂质代谢、胰岛素敏感性、炎症和血压调节中起着关键作用,因而近年来倍受关注。越来越多的研究表明,PPARs与代谢综合征,包括胰岛素抵抗、糖耐量受损、2型糖尿病、肥胖、高脂血症、高血压病、动脉粥样硬化和蛋白尿之间存在因果关系。重要的是,PPARα的激动剂如贝丁酸类降脂药(Fibrate)和PPARγ的激动剂如噻唑烷二酮(Thiazolidinedione,TZD)均已被证实有改善代谢综合征的作用。此外,三种PPAR亚型在2型糖尿病及糖尿病肾病的发展中均有重要作用。不断增加的证据提示,PPARs有可能成为代谢综合征及其相关并发症的潜在治疗靶点。本文将就PPARs的生物学活性、配体选择性和生理学功能作一综述,并对其在代谢综合征发病机制中的作用和PPAR配体对2型糖尿病的治疗效用进行重点讨论。     

PPAR基因与脂肪代谢调控

过氧化物酶体增值剂激活受体(PPARs)基因属于类固醇/甲状腺/维甲酸受体超家族,有3个亚型,即：PPAR-α、PPAR-β和PPAR-γ。PPARs具有多种生物学功能,如增强机体对胰岛素敏感性,调节体内糖平衡等,尤其在脂肪分化、生成等多方面起到重要作用,是目前的研究热点,文章从PPARs基因的结构,表达及功能等方面讨论了其与脂肪代谢调控的关系。     

PPARα,γ和δ:胰岛素抵抗治疗的靶点

胰岛素抵抗(insulin resistance,IR)是指外周组织对胰岛素的反应敏感性降低,是肝脏疾病和心血管病发生的共同基础,常常是高脂血症和2型糖尿病发病的前奏.过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptors,PPARs)属于核受体超家族的成员.PPARs激动剂可通过多种途径改善胰岛素敏感性,例如调节糖脂代谢、抗炎作用以及间接地改善氧化应激状态.这篇综述主要是回顾IR的病理机制及其治疗靶点:PPARα,δ和γ,并阐明针对此类靶点的胰岛素增敏药物的信号转导通路.     

PPARs in the brain

The biology of peroxisome proliferator activated receptors (PPARs) in physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Recently it became clear that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular, the PPARgamma isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that have an inflammatory component. Activation of all PPAR isoforms, but especially of PPARgamma, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in Multiple Sclerosis patients. Likewise, Alzheimer's disease has a prominent inflammatory component that arises in response to neurodegeneration and to extracellular deposition of beta-amyloid peptides. The fact that non steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop Alzheimer's disease, while they also bind to and activate PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARgamma. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using Alzheimer disease related transgenic cellular and animal models. The ability of PPAR agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin sensitizing effects may account for the observed effects. A number of clinical trials employing PPAR agonists have yielded promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative diseases such as Parkinson's and Amyotrophic lateral sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet it is not clear whether reduction of inflammation or additional mechanisms account for the observed neuroprotection. Less is known about the physiological role of PPARs for brain development, maintenance and function. Lesions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and function.     

Pharmacology of PPARalpha, PPARgamma and dual PPARalpha/gamma agonists in clinical development

Cardiovascular diseases (CVD) remain the leading cause of mortality in the western societies. Several risk factors predispose to CVD including diabetes, obesity, insulin resistance, dyslipidemia and hypertension. Various pharmacological therapies have been developed to control the risk factors associated to CVD. Fibrates are able to correct dyslipidemia, therefore decreasing CVD risk. Thiazolidinediones (TZD) or glitazones by increasing insulin sensitivity decrease plasma glucose levels in diabetic patients. Both fibrates and TZD activate the peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors that play a central role in the control of lipid and glucose metabolism. In this review, we will discuss the mode of action of fibrates and TZD and we will present an overview on PPAR ligands under development.     

A defect in the activity of Delta6 and Delta5 desaturases may be a factor predisposing to the development of insulin resistance syndrome

GLUT-4 (glucose transporter) receptor, tumor necrosis factor-alpha (TNF-alpha), interleukins-6 (IL-6), daf-genes and PPARs (peroxisomal proliferation activator receptors) play a role in the development of insulin resistance syndrome and associated conditions. But, the exact interaction between these molecules/factors and the mechanism(s) by which they produce insulin resistance syndrome is not clear. I propose that a defect in the activity of the enzymes Delta6 and Delta5 desaturases that are essential for the formation of long chain metabolites of essential fatty acids, linoleic acid and alpha-linolenic acid, is a factor in the development of insulin resistance syndrome. Long chain polyunsaturated fatty acids (LCPUFAs) increase cell membrane fluidity and enhance the number of insulin receptors and the affinity of insulin to its receptors; suppress TNF-alpha, IL-6, macrophage migration inhibitory factor (MIF) and leptin synthesis; increase the number of GLUT-4 receptors, serve as endogenous ligands of PPARs, modify lipolysis, and regulate the balance between pro- and anti-oxidants, and thus, play a critical role in the pathogenesis of insulin resistance. In the nematode, Caenorhabditis elegans, the protein encoded by daf-2 is 35% identical to the human insulin receptor; daf-7 codes a transforming growth factor-beta (TGF-beta) type signal and daf-16 enhances superoxide dismutase (SOD) expression. Melatonin has anti-oxidant actions similar to daf-16, TGF-beta and SOD. Calorie restriction enhances the activity of Delta6 and Delta5 desaturases, melatonin production, decreases daf-2 signaling, free radical generation, and augments anti-oxidant defenses that may explain the beneficial effect of diet control in the management of obesity, insulin resistance, and type II diabetes mellitus. These evidences suggest that the activities of Delta6 and Delta5 enzymes play a critical role in the expression and regulation of GLUT-4, TNF-alpha, IL-6, MIF, daf-genes, melatonin, and leptin by modulating the synthesis and tissue concentrations of LCPUFAs. Caloric restriction delays ageing by activating Sir 2 deacetylase in yeast, and expression of Sir 2 (SIRT1) in human cells. Both insulin and insulin-like growth factor-1 (IGF-1) attenuated this response. SIRT1 sequesters the proapoptotic factor Bax, prevents stress-induced apoptosis of cells, and thus, prolongs survival. In addition, SIRT1 repressed PPAR-gamma, and overexpression of SIRT1 attenuated adipogenesis, and upregulation of SIRT in differentiated fat cells triggered lipolysis and loss of fat, events that are known to attenuate insulin resistance and prolong life span. It remains to be seen whether LCPUFAs have a regulatory role in SIRT1 expression and control Sir 2 deacetylase activity. Thus, calorie restriction or reduced food intake has a role not only in the pathobiology of insulin resistance, but also in other associated conditions such as obesity, type II diabetes mellitus, ageing, and longevity.     

Peroxisome proliferator-activated receptors modulate proliferation and angiogenesis in human endometrial carcinoma

Peroxisome proliferator-activated receptors (PPAR) and retinoid X receptors (RXR) are implicated in the development of several obesity-related cancers. Little is known of either the expression or function of PPARs and RXRs in endometrial cancer although this increasingly common disease is highly associated with both obesity and insulin resistance. We investigated the expression of PPAR and RXR subtypes in human endometrial cancers and normal endometrium with immunoblotting and immunohistochemistry and subsequently showed PPAR/RXR binding preferences by coimmunoprecipitation. To determine the functions of PPARs within the endometrium, we investigated proliferation, apoptosis, PTEN expression, and secretion of vascular endothelial growth factor (VEGF) in endometrial cell lines after reducing the expression of PPARα and PPARγ with antisense RNA. The functional effects of PPAR ligands were also investigated in vitro. We identified differential expression of PPAR and RXR subtypes in endometrial cancers and discovered that PPARγ expression correlated with expression of PTEN. PPARα activation influences endometrial cell growth and VEGF secretion. PPARγ activation reduces proliferation of endometrial cells via regulation of PTEN and appears to reduce VEGF secretion. We conclude that the PPAR/RXR pathway contribute to endometrial carcinogenesis by control of PTEN expression and modulation of VEGF secretion. We propose that PPAR ligands should be considered for clinical investigation in early phase studies of women with endometrial cancer.     

Defining the molecular nexus of cancer, type 2 diabetes and cardiovascular disease

The metabolic syndrome is characterized by a state of metabolic dysfunction resulting in the development of several chronic diseases that are potentially deadly. These metabolic deregulations are complex and intertwined and it has been observed that many of the mechanisms and pathways responsible for diseases characterizing the metabolic syndrome such as type 2 diabetes and cardiovascular disease are linked with cancer development as well. Identification of molecular pathways common to these diverse diseases may prove to be a critical factor in disease prevention and development of potential targets for therapeutic treatments. This review focuses on several molecular pathways, including AMPK, PPARs and FASN that interconnect cancer development, type 2 diabetes and cardiovascular disease. AMPK, PPARs and FASN are crucial regulators involved in the maintenance of key metabolic processes necessary for proper homeostasis. It is critical to recognize and identify common pathways deregulated in interrelated diseases as it may provide further information and a much more global picture in regards to disease development and prevention. Thus, this review focuses on three key metabolic regulators, AMPK, PPARs and FASN, that may potentially serve as therapeutic targets.     

Peroxisome proliferator-activated receptors and cardiovascular remodeling

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: alpha, beta/delta, and gamma. The better known are PPAR-alpha and PPAR-gamma, which may be activated by different synthetic agonists, although the endogenous ligands are unknown. PPAR-alpha is involved in fatty acid oxidation and expressed in the liver, kidney, and skeletal muscle, whereas PPAR-gamma is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable amounts in cardiovascular tissues, including endothelium, smooth muscle cells, macrophages, and the heart. The activators of PPAR-alpha (fibrates) and PPAR-gamma (thiazolidinediones or glitazones) antagonized the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators lowered blood pressure, induced favorable effects on the heart, and corrected vascular structure and endothelial dysfunction in several rodent models of hypertension. Activators of PPARs may become therapeutic agents useful in the prevention of cardiovascular disease beyond their effects on carbohydrate and lipid metabolism. Some side effects, such as weight gain, as well as documented aggravation of advanced heart failure through fluid retention by glitazones, may, however, limit their therapeutic application in prevention of cardiovascular disease.     

Peroxisome proliferator-activated receptor alpha in metabolic disease, inflammation, atherosclerosis and aging.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors which are activated by fatty acids and derivatives. The PPAR alpha form has been shown to mediate the action of the hypolipidemic drugs of the fibrate class on lipid and lipoprotein metabolism. PPAR alpha activators furthermore improve glucose homeostasis and influence body weight and energy homeostasis. It is likely that these actions of PPAR alpha activators on lipid, glucose and energy metabolism are, at least in part, due to the increase of hepatic fatty acid beta-oxidation resulting in an enhanced fatty acid flux and degradation in the liver. Moreover, PPARs are expressed in different immunological and vascular wall cell types where they exert anti-inflammatory and proapoptotic activities. The observation that these receptors are also expressed in atherosclerotic lesions suggests a role in atherogenesis. Finally, PPAR alpha activators correct age-related dysregulations in redox balance. Taken together, these data indicate a modulatory role for PPAR alpha in the pathogenesis of age-related disorders, such as dyslipidemia, insulin resistance and chronic inflammation, predisposing to atherosclerosis.     

Mitochondrial dysfunction by synthetic ligands of peroxisome proliferator activated receptors (PPARs)

PPARs are a class of nuclear receptors involved in lipid and glucidic metabolism, immune regulation and cell differentiation. This spectrum of biological activities stimulated pharmacological research to synthetize different molecules with PPARs binding activity with beneficial therapeutic effects. As a matter of fact, some synthetic PPAR-ligands have been already employed in pharmacotherapy: PPAR-alpha ligands, such as fibrates, are used in hyperlipidemias and thiazolidinediones, mainly PPAR-gamma ligands, are employed as insulin sensitizers. However, both classes of drugs showed pharmacotoxicological profiles which cannot be fully ascribed to activation of their specific receptors and which are causing a growing incidence of dramatic side effects (rhabdomyolysis, acute liver failure, heart failure, etc.). A re-evaluation of the biological activities of PPAR synthetic ligands, in particular of the mitochondrial dysfunction based on a rotenone-like Complex I partial inhibition and of its consequent metabolic adaptations, seems to explain some of the pathophysiologic aspects of PPARs allowing a better definition of the therapeutic properties of the so-called PPAR-ligands.     

Macrophage fatty acid oxidation and its roles in macrophage polarization and fatty acid-induced inflammation

Recent research considerably changed our knowledge how cellular metabolism affects the immune system. We appreciate that metabolism not only provides energy to immune cells, but also actively influences diverse immune cell phenotypes. Fatty acid metabolism, particularly mitochondrial fatty acid oxidation (FAO) emerges as an important regulator of innate and adaptive immunity. Catabolism of fatty acids also modulates the progression of disease, such as the development of obesity-driven insulin resistance and type II diabetes. Here, we summarize (i) recent developments in research how FAO modulates inflammatory signatures in macrophages in response to saturated fatty acids, and (ii) the role of FAO in regulating anti-inflammatory macrophage polarization. In addition, we define the contribution of AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptors (PPARs), in controlling macrophage biology towards fatty acid metabolism and inflammation.