AgiAl Nuclear Receptor Research Publishing House Vol. 2 (2015), Article ID 101188, 30 pages doi:10.11131/2015/101188 http://www.agialpress.com/ Review Article Peroxisome Proliferator-Activated Receptors: Features, Functions, and Future Jihan Youssef and Mostafa Badr University of Missouri-Kansas City, Kansas City, MO 64108, USA Corresponding Author: Mostafa Badr; email: [email protected] Received 26 May 2015; Accepted 30 August 2015 Editor: Christopher Corton Copyright © 2015 Jihan Youssef and Mostafa Badr. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract. In this review, the history of the peroxisome proliferator-activated receptors (PPAR훼, PPAR훽/훿 and PPAR훾) discovery is briefly traced and major features of their structure and posttranslational modifications are presented. Furthermore, an overview of PPAR coactivators and corepressors as well as of endogenous and exogenous ligands is discussed. We have also summarized significant efforts underway to develop more effective and safer PPAR modulators as therapeutic agents to treat diseases such as diabetes, cancer, atherosclerosis, and inflammation. Finally, we share a hypothesis proposing how PPARs may control inflammatory events. Keywords: PPARs; nuclear receptors; ligands; inflammation; endosalicylates 1. Introduction various tissues. Among other effects, PPAR훼 control lipid metabolism and inflammatory processes, while PPAR훽/훿 In the course of attempting to delineate the mechanism(s) regulates glucose utilization, cell differentiation and inflam- by which some chemicals induce peroxisome proliferation in mation. PPAR훾 is involved in adipocyte differentiation, rodents, a receptor, peroxisome proliferator-activated recep- glucose metabolism and inflammatory pathways [3]. tor (mouse PPAR훼), was discovered [1]. Shortly thereafter, The receptor activity is modified posttranslationally by two more PPAR subtypes, PPAR훽/훿 and PPAR훾, were phosphorylation, sumoylation and ubiquitination as well as identified. Although the three receptor subtypes share a high controlled by a myriad of coregulators [4–6]. Research in degree of homology, they differ in tissue distribution and the field continues to reveal new roles for these receptors in level of expression as well as in ligand specificity [2]. a variety of normal and disease conditions. In this review As research in the field progressed, it was discovered we trace the history of the receptor discovery and describe that PPARs regulate a variety of biological processes in their identified features and posttranslational modifications. 2 Nuclear Receptor Research Furthermore, an overview of PPAR coactivators and core- at position 131 (R131Q) [20, 21]. These variants possibly pressors as well as endogenous and exogenous ligands is account for species-related differences in the response to presented. We also present a plausible hypothesis stipulating PPAR훼 activators (Table 3). It has also been suggested how PPARs may control inflammation. that the PPAR훼 L162 V polymorphism is involved in liver tumor progression in patients with hepatocellular carcinoma [22]. Another variant, PPAR훼 V227A, is considered a 2. Historical Perspective major polymorphism in the Japanese population [23]. An association has been described between this polymorphism It has been well documented that an increase in size and the pathogenesis of non-alcoholic fatty liver disease as and/or number of peroxisomes in the rodent liver is caused well as with a protective role against obesity [24]. by a group of structurally diverse chemicals known as peroxisome proliferators [7]. However, despite dissimilarity 3.1.2. PPAR훽/훿.A 3′ splice variant of human PPAR훿 in the structure of these chemicals (Table 1), a receptor- (PPAR훿2) has been reported [25]. This variant is a potential mediated mechanism for peroxisome proliferation was pos- repressor of the PPAR훿 wild type receptor. The existence of tulated [8]. A peroxisome proliferator-binding protein was a PPAR훿 +294T/C polymorphism (Table 2) has also been later purified from rat liver cytosol and was identified as a demonstrated [26], and this polymorphism is associated, in dimer protein which has a molecular weight of 140,000– humans, with elevated levels of LDL and apolipoprotein 160,000 KDa [9]. This protein was capable of binding to B, lower levels of HDL and higher risks of coronary peroxisome proliferators structurally related to clofibrate and heart disease [27–29]. The +294T/C polymorphism of this was suggested to play an important role in the regulation receptor may be linked to an increase in fasting glucose levels of peroxisome proliferator-induced pleiotropic response [9]. in women with polycystic ovary syndrome [30]. Further analysis of the isolated protein revealed that it was homologous with the heat shock protein HSP70 [10]. 3.1.3. PPAR훾. It has been reported that alternate transcription Eventually, PPAR훼 was discovered [1] and subsequent start sites and alternative splicing are responsible for the studies indicated that Hsp72 and PPAR form a complex in generation of four types of PPAR훾 mRNA. However, it is vivo, suggesting that this protein may play a role in the believed that mRNAs of PPAR훾 1, 3, and 4 are translated activity of PPARs [11]. into an identical protein [31, 32]. The presence of PPAR훾2 The cloned receptor was found to possess structural Pro12Ala variant (Table 2) in humans has been reported similarities to the steroid hormone receptors. Since the [33]. An association of this polymorphism with type2 identified receptor was thought to mediate the peroxisome diabetes, insulin resistance and obesity is controversial where proliferative response to peroxisome proliferating chemicals, conflicting data, regarding its effect in different populations, the receptor was named peroxisome proliferator-activated are available [34–38]; with gender differences as well as receptor (PPAR). genetic factors potentially contributing to the discrepancy of Following the discovery of mouse PPAR훼, the receptor reported results [39–41]. A meta-analysis study shows that was identified in other species, including rat [12] and human the Ala allele is associated with a lower risk of developing [13]. In addition, three related Xenopus receptors were type2 diabetes in Caucasians and with improved insulin cloned, PPAR훼, PPAR훽 and PPAR훾 [14]. PPAR훿 was later sensitivity in overweight individuals [42]. identified in human and was found to be closely related Studies have suggested that PPAR훾 Pro12Ala expression to PPAR훽 described earlier in Xenopus. These receptors may increase the risk of cognitive impairment and dementia bind to and are activated by numerous ligands, including upon the development of diabetes [43], and this polymor- fatty acids, eicosanoids and numerous xenobiotics; some phism may also play a role in the development of dementia at of which possess therapeutic value [15–17]. Structures of a younger age [44]. In addition, an association of this poly- representative ligands are presented in Figures 1 and 2. morphism with peripheral arterial disease has been reported [45]. Furthermore, involvement of the PPAR훾 Pro12Ala polymorphism has been mentioned in the development of 3. PPARs: Genomics and Proteomics gastric cancer [46–48] as well as endometriosis [49]. Another frequent PPAR훾 polymorphism (C1431T) was 3.1. Genomics. identified and found to be associated with higher plasma 3.1.1. PPAR훼. Several genetic variants of PPAR훼 have been leptin levels [50]. While some studies reported no association identified (Table 2). A variant lacking exon 6, found in human between this polymorphism and body mass index (BMI) tissues, is generated by alternative splicing [18, 19]. The [50, 51], other investigations linked C1431T to higher BMI corresponding protein of this variant is localized exclusively values [52]. Studies have also reported opposing effects of in the cytoplasm and inhibits wild type PPAR훼 protein C1431T polymorphism and Pro12Ala polymorphism on BMI activity [18]. In addition, the presence of two other PPAR훼 and diabetes [53, 54]. variants has been revealed; one with a mutation at codon In addition to the above mutations, a PPAR훾 C190S 162 (L162V) and the other with a less frequent mutation mutation has been associated with partial lipodystrophy AgiAl Publishing House | http://www.agialpress.com/ Nuclear Receptor Research 3 Table 1: Representative Peroxisome Proliferators. Fibrates Nonfibrates Miscellaneous Bezafibrate Phthalic acid esters Aspirin Ciprofibrate Mono (2-ethylhexyl) Phthalate Dehydroepiandrosterone Clofibrate Di (2-ethylhexyl) Phthalate Ethanol Perfluorinated fatty acids Valproic acid Perfluorooctanoic acid Perfluorodecanoic acid O O OH O O O CH 3 O H C CH CI 3 3 Clo brate MEHP (a) COOH COOH Oleic acid Arachidonic acid OH OH COOH COOH O Leukotriene B 4 15-Deoxy-Δ12, 14-prostaglandin J 2 (b) Figure 1: Representative PPAR Agonists: A, exogenous; B, endogenous. Table 2: Common PPAR Variants Table 3: Species Differences in Hepatic Peroxisomal 훽-Oxidation in Response to PPAR훼 Activators in vitroa. Variant Reference PPAR훼 Drug Rat Rhesus Monkey L 162 V [20, 22] Bezafibrateb 7.99 1.39 R 131 Q [20, 21] Ciprofibrateb 9.95 1.77 V 227 A [23, 24] LY 17,1883c 5.44 1.44 PPAR훽/훿 aFold increase in hepatic peroxisomal 훽-oxidation activity; +294T/C [26–30] b200 휇M for 3 days; c100 휇M for 3 days [300]. PPAR훾 P 12 A [33] [55]. Other mutations, R166W in PPAR훾1 and R194W in C 1431 T [50] PPAR훾2, are