Peroxisome Proliferator-Activated Receptor (PPAR)
PPARs were initially discovered while delineating mechanisms that induce peroxisome proliferation in rodents, hence the name of peroxisome proliferator-activated receptor. PPARα was the first identified isoform cloned from a mouse liver complementary DNA library in 1990 from researchers working on the mechanisms implicated in the promoting action of a variety of chemicals on peroxisomal proliferation in the rodent liver (Issemann and Green 1990). The identified protein presented a high degree of similarity with several members of the nuclear hormone receptor superfamily and was highly expressed in liver, kidney, heart, and brown adipose tissue. Τhe other two PPAR isoforms called PPARβ/δ and PPARγ were later identified in Xenopus laevis (Dreyer et al. 1992), human (Greene et al. 1995), and mouse (Chen et al. 1993).
PPAR Mechanism of Action
Non-genomic pathways for PPAR actions usually include interaction of these receptors with second messengers or extranuclear molecules such as kinases or phosphatases that affect signaling (Cantini et al. 2010).
Posttranslational Regulation of PPARs
PPARs are usually posttranslationally modified by phosphorylation, sumoylation, ubiquitination, and nitration. Modification by phosphorylation has been shown to regulate PPARα and PPARγ activity but not PPARβ/δ. The kinases involved are MAPKs as well as PKA, PKC, and GSK3, while the phosphorylation site dictates the outcome of this effect leading either to enhanced transcriptional activity or increased receptor degradation (Bugge and Mandrup 2010; Luconi et al. 2010). Sumoylation and ubiquitination are additional mechanisms of PPAR regulation that correlate with phosphorylation. Specifically, phosphorylation may reduce or enhance PPARα ubiquitination, depending on the phosphorylation site, whereas sumoylation could repress PPARγ activity (Bugge and Mandrup 2010). The nitration of PPARs on tyrosine residues is usually described on conditions such as inflammation where nitric oxide levels are increased (Luconi et al. 2010). In this case the receptor activity is inhibited due to the attenuation of the ligand-induced nuclear translocation of PPAR. The activity of PPARs is also regulated by their intracellular localization. The nuclear distribution of the receptor is correlated to the genomic effects, while the shift from nucleus to cytosol enhances the non-genomic functions (Cantini et al. 2010, Luconi et al. 2010). From this point of view, it has been reported that phosphorylation or sumoylation of PPARγ results in the export of the receptor from the nucleus to the cytosol (Bugge and Mandrup 2010), while PPARs have been also detected at the plasma membrane, subjecting the receptor to the influence of extracellular signals (Luconi et al. 2010).
Natural and synthetic ligands of PPARs
Physiological substances acting as natural ligands
Synthetic selective ligands
Unsaturated and saturated fatty acids
8-S-hydroxy-eicosatetraenoic acid (8-S-HETE)
Leucotriene B4 (LTB4)
Arachidonate monooxygenase metabolite epoxyeicosatrienoic acids
Fibrates (clofibrates, fenofibrate)
Unsaturated and saturated fatty acids
Unsaturated fatty acids
12- and 15-HETE
Glitazones (rosiglitazone, pioglitazone, ciglitazone, troglitazone)
Physiological Functions of PPARs
The three members of the PPAR family identified so far, α (alpha), β/δ (beta/delta), and γ (gamma), are encoded by separate genes and have distinct but overlapping spatial, temporal, and regulated expression patterns (Braissant et al. 1996). They are mainly known for their roles in the transcriptional regulation of fatty acid and lipoprotein metabolism and glucose homeostasis (Desvergne and Wahli 1999). PPARα is highly expressed in hepatocytes, cardiac myocytes, the cortex of the kidney, and skeletal muscle (e.g., tissues with significant capacity of oxidation of fatty acids), and it primarily regulates fatty acid transport, esterification, and oxidation. PPARγ is predominantly expressed in brown and white adipose tissue and to a lesser extent in immune cells (such as monocytes, macrophages, and the plates of Peyer) and intestinal mucosa. It regulates adipocyte differentiation, lipid storage, and insulin sensitivity (Feige et al. 2006). PPARβ/δ is expressed in most tissues with particular abundance in cardiac and skeletal muscle where it controls FA oxidation and glucose uptake (Neels and Grimaldi 2014).
However, since their discovery, PPARs have been also shown to influence several other biological processes such as inflammatory responses, cellular proliferation, differentiation, and apoptosis in various cell types (Menéndez-Gutiérrez et al. 2012; Barlaka et al. 2016). In this respect, PPARs have been shown to be involved in the regulation of the expression of pro-inflammatory cytokines or adhesion molecules (Fuentes et al. 2010).
PPAR Signaling in Disease
PPARs are a pharmacological target for the treatment of metabolic disorders such as diabetes or dyslipidemia. Several synthetic agonists of PPARα and PPARγ, such as fibrates or glitazones, are known as marketed drugs and are used in the treatment of hypertriglyceridemia and diabetes mellitus, respectively (Lalloyer and Staels 2010).
In the cardiovascular system, PPARs have emerged as important therapeutic targets, given the role of metabolism imbalance under pathological states of the heart, and accumulating evidence highlights their protective role in the improvement of cardiac function under diverse pathological settings including cardiac hypertrophy and heart failure (Finck 2007). Apart from their characteristic roles in metabolism, PPARs regulate non-metabolic signaling pathways in the heart, including extracellular matrix remodeling, antioxidant systems, and inflammation, and have been shown to exert important functions in atherosclerosis, cardiac fibrosis, cardiac ischemia/reperfusion injury, and infarct healing (van Bilsen and van Nieuwenhoven 2010; Ravingerova et al. 2011; Barlaka et al. 2016). Moreover, studies have identified a role for PPARα in cell cycle regulation/proliferation and angiogenesis, which potentially impact the pathogenesis of ischemic heart disease and other cardiac pathologies (Couffinhal et al. 2009).
Although there have been intensive research, the role of PPARs in cancer still remains controversial. In preclinical studies, PPARs were shown to both promote and suppress neoplasia. This contradiction suggests that the effects of PPARs are complex and may depend on several factors such as the different cell types present in the tumor, their differentiation state, or the diverse characteristics of the animal models studied (Michalik et al. 2004; Menéndez-Gutiérrez et al. 2012). The effect of PPARs on cancer is also associated with their effect on inflammation and angiogenesis, two processes that strongly influence tumor growth (Karin 2005).
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors, belong to the nuclear hormone receptor superfamily regulating expression of genes involved in different aspects of lipid and lipoprotein metabolism, glucose homeostasis, and inflammation. PPARα is highly expressed in tissues such as the liver, muscle, kidney, and heart, where it stimulates mitochondrial fatty acid oxidation. PPARγ is predominantly expressed in adipose tissue triggering adipocyte differentiation and promoting lipid storage. The less explored PPARβ/δ is expressed in most tissues with particular abundance in cardiac and skeletal muscle where it controls fatty acid oxidation and glucose uptake. Other non-metabolic functions of PPARs include regulation of inflammatory and immune responses, cellular antioxidant defense, differentiation, and apoptosis. Fatty acids and eicosanoids are natural PPAR ligands, whereas synthetic ligands have been also developed, and among them are known marketed drugs. The hypolipidemic fibrates and the antidiabetic glitazones are synthetic ligands for PPARα and PPARγ, respectively. PPARs are important targets in the treatment of metabolic disorders such as dyslipidemias, insulin resistance, and type 2 diabetes mellitus and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis. Recent advances demonstrate the protective role of PPARs in cardiac dysfunction, namely, ischemia/reperfusion injury, hypertrophy, and cardiac failure, while their role in cancer is still a matter of controversy. The abundant pleiotropic actions of PPARs make them interesting therapeutic targets for the treatment of various pathological conditions.
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