Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Peroxisome Proliferator-Activated Receptor (PPAR)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101829

Synonyms

Historical Background

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 Structure

PPARs’ basic structure includes several domains which interact with each other for the receptor function (Fig. 1). A N-terminal region (A/B domain) holds a weak ligand-independent transactivating function (AF-1) and is basically responsible for the subtype transcriptional activity of PPAR target genes in the absence of a ligand (Hummasti and Tontonoz 2006) while being a target of kinase phosphorylation (Luconi et al. 2010). The DNA-binding domain (DBD, C domain) contains two highly conserved zinc finger-binding motifs and amino acid motifs that facilitate binding to PPAR response elements (PPREs) located in the promoter region of target genes. This region is also involved in co-activator binding and dimerization of PPARs with RXRs, a process necessary for transcriptional activation (Feige et al. 2005). The hinge region (D domain) acts as a connection between DBD and LBD (ligand-binding domain) and as a docking domain for co-activators. The carboxyl terminal (E/F domain) is the largest domain in the receptor, and its structure is common to the three PPAR subtypes, while small differences in the features of binding pockets between the three isoforms may play a major role in determining ligand-binding selectivity. It contains the hydrophobic ligand-binding domain (LBD) to which ligands bind to either activate or repress the receptor transactivation (Xu et al. 2001). Moreover the LBD domain is important for heterodimerization and interaction with transcriptional cofactors (Zoete et al. 2007).
Peroxisome Proliferator-Activated Receptor (PPAR), Fig. 1

PPAR nuclear receptor structure. General PPAR structure includes four distinct structural domains: A/B domain refers to AF-1 ligand-independent transactivation domain, C domain corresponds to the DNA-binding domain that promotes binding to PPREs in the promoter region of target genes through zinc finger-binding motifs. D is the hinge domain that connects C and E/F domain. The latter (E/F domain) includes the ligand-binding domain

PPAR Mechanism of Action

Several postulates have been suggested to explain PPAR-mediated action. It is generally accepted that besides modulating the expression of specific target genes, PPARs also have non-genomic effects. It is established that PPARs heterodimerize with the receptor of 9-cis-retinoic acid (RXR) prior to ligand binding thus leading to a complex formation required for binding to specific DNA sequences in the promoter region of target genes referred to as PPAR response elements (PPREs). Ligand binding to the receptor leads to conformational changes that can facilitate recruitment of co-activators and release of co-repressors (Feige et al. 2006). It is suggested that nuclear receptors usually remain bound to co-repressors until conformational changes caused by ligand binding lead to dissociation of co-repressors and subsequent binding of co-activators (Mitro et al. 2013). Moreover, PPARs can negatively regulate the expression of genes without binding to DNA or inhibit the activities of other transcription factors by direct interaction via a mechanism known as ligand-dependent trans-repression (Daynes and Jones 2002). Trans-repression may occur either through physical interaction of PPARs with other transcription factors or co-activators or through modulation of kinase activity preventing activation of downstream transcription factors (Fig. 2).
Peroxisome Proliferator-Activated Receptor (PPAR), Fig. 2

Molecular modes of action of PPARs. Simplified scheme illustrating transactivation and trans-repression of target genes. PPAR, peroxisome proliferator-activated receptors; NF-κB-RE, nuclear factor-κB response element; PPRE, PPAR response element; RXR, retinoid X receptor; STATs, signal transducer and activator of transcription; TRE, TPA (12-O-tetradecanoylphorbol-13-acetate) response element; ISGF-RE, interferon-stimulated gene factor response element

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).

PPAR Ligands

All PPAR isoforms are known to be activated by polyunsaturated fatty acids and arachidonic acid derivatives (Grimaldi 2007). Physiological substances such as eicosanoids, including 8-S-hydroxyeicosatetraenoic acid (8-S-HETE), leukotriene B4 (LTB4), and arachidonate monooxygenase metabolite epoxyeicosatrienoic acids, are potent activators of PPARα (Feige et al. 2006). Derivatives of arachidonic acid called prostanoids, such as 15-deoxy-12,14-prostaglandin J2 (15d-PGJ2) and 12- and 15-hydroxy-eicosatetraenoic acid (12- and 15-HETE), are produced during the lipoxygenase pathway and have been shown to activate PPARγ (Theocharis et al. 2004). Moreover substances extracted by plants such as flavonoids apigenin and hesperidin are also identified as strong PPARγ agonists (Salam et al. 2008). With respect to PPARβ/δ, natural ligands prostacyclin (PGI2) and 4-hydroxynonenal (4-HNE) which result from lipid peroxidation have been proposed to activate this isoform (Gupta et al. 2000, Coleman et al. 2007). Various synthetic ligands (Table 1) have been identified to selectively activate PPARs and have contributed to studies concerning PPAR roles in pathology. Among those, the well-established fibrates are used in hyperlipidemia treatment, and glitazones are effective antidiabetic drugs (Lalloyer and Staels 2010).
Peroxisome Proliferator-Activated Receptor (PPAR), Table 1

Natural and synthetic ligands of PPARs

PPAR isoform

Physiological substances acting as natural ligands

Synthetic selective ligands

PPARα

Unsaturated and saturated fatty acids

8-S-hydroxy-eicosatetraenoic acid (8-S-HETE)

Leucotriene B4 (LTB4)

Arachidonate monooxygenase metabolite epoxyeicosatrienoic acids

WY-14643

Fibrates (clofibrates, fenofibrate)

PPARβ/δ

Unsaturated and saturated fatty acids

PGI2

4-HNE

GW0742

GW501516

LC1765

PPARγ

Unsaturated fatty acids

15d-PGJ2

12- and 15-HETE

Flavonoids

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

Metabolic Disorders

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).

Cardiovascular Disease

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).

Cancer

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).

Summary

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.

References

  1. Barlaka E, Galatou E, Mellidis K, Ravingerova T, Lazou A. Role of pleiotropic properties of peroxisome proliferator-activated receptors in the heart: focus on the nonmetabolic effects in cardiac protection. Cardiovasc Ther. 2016;34(1):37–48.PubMedCrossRefGoogle Scholar
  2. Braissant O, Foufelle F, Scotto C, Dauça M, Wahli W. Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, −β, and -γ in the adult rat. Endocrinology. 1996;137(1):354–66.PubMedCrossRefGoogle Scholar
  3. Bugge A, Mandrup S. Molecular mechanisms and genome-wide aspects of PPAR subtype specific transactivation. PPAR Res. 2010; 169506: 1–12.Google Scholar
  4. Cantini G, Lombardi A, Borgogni E, et al. Peroxisome proliferator-activated receptor gamma (PPARgamma) is required for modulating endothelial inflammatory response through a nongenomic mechanism. Eur J Cell Biol. 2010;89:645–53.PubMedCrossRefGoogle Scholar
  5. Chen F, Law SW, O’Malley BW. Identification of two mPPAR related receptors and evidence for the existence of five subfamily members. Biochem Biophys Res Commun. 1993;196:671–7.PubMedCrossRefGoogle Scholar
  6. Coleman JD, Prabhu KS, Thompson JT, Reddy PS, Peters JM, Peterson BR, Reddy CC, Vanden Heuvel JP. The oxidative stress mediator 4-hydroxynonenal is an intracellular agonist of the nuclear receptor peroxisome proliferator activated receptor-beta/delta (PPARbeta/delta). Free Radic Biol Med. 2007;42:1155–64.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Couffinhal T, Dufourcq P, Barandon L, Leroux L, Duplaa C. Mouse models to study angiogenesis in the context of cardiovascular diseases. Front Biosci. 2009;14:3310–25.CrossRefGoogle Scholar
  8. Daynes RA, Jones DC. Emerging roles of PPARs in inflammation and immunity. Nat Rev Immunol. 2002;2:748–59.PubMedCrossRefGoogle Scholar
  9. Desvergne B, Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999;20:649–88.PubMedPubMedCentralGoogle Scholar
  10. Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W. Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992;68:879–87.PubMedCrossRefGoogle Scholar
  11. Feige JN, Gelman L, Tudor C, Engelborghs Y, Wahli W, Desvergne B. Fluorescence imaging reveals the nuclear behavior of peroxisome proliferator-activated receptor/retinoid X receptor heterodimers in the absence and presence of ligand. J Biol Chem. 2005;280:17880–90.PubMedCrossRefGoogle Scholar
  12. Feige JN, Gelman L, Michalik L, Desvergne B, Wahli W. From molecular action to physiological outputs: peroxisome proliferator-activated receptors are nuclear receptors at the crossroads of key cellular functions. Prog Lipid Res. 2006;45:120–59.PubMedCrossRefGoogle Scholar
  13. Finck BN. The PPAR regulatory system in cardiac physiology and disease. Cardiovasc Res. 2007;73(2):269–77.PubMedCrossRefGoogle Scholar
  14. Fuentes L, Roszer T, Ricote M. Inflammatory mediators and insulin resistance in obesity: role of nuclear receptor signaling in macrophages. Mediators Inflamm. 2010;2010:219583.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995;4:281–99.PubMedPubMedCentralGoogle Scholar
  16. Grimaldi PA. Peroxisome proliferator-activated receptors as sensors of fatty acids and derivatives. Cell Mol Life Sci. 2007;64:2459–64.PubMedCrossRefGoogle Scholar
  17. Gupta RA, Tan J, Krause WF, et al. Prostacyclin-mediated activation of peroxisome proliferator-activated receptor delta in colorectal cancer. Proc Natl Acad Sci USA. 2000;97:13275–80.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Hummasti S, Tontonoz P. The peroxisome proliferator activated receptor N-terminal domain controls isotype selective gene expression and adipogenesis. Mol Endocrinol. 2006;20:1261–75.PubMedCrossRefGoogle Scholar
  19. Issemann I, Green S. Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990;347:645–50.PubMedCrossRefGoogle Scholar
  20. Karin M. Inflammation and cancer: the long reach of Ras. Nat Med. 2005;11(1):20–1.PubMedCrossRefGoogle Scholar
  21. Lalloyer F, Staels B. Fibrates, glitazones, and peroxisome proliferator-activated receptors. Arterioscler Thromb Vasc Biol. 2010;30:894–9.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Luconi M, Cantini G, Serio M. Peroxisome proliferator activated receptor gamma (PPARgamma): is the genomic activity the only answer? Steroids. 2010;75:585–94.PubMedCrossRefGoogle Scholar
  23. Menéndez-Gutiérrez MP, Roszer M, Ricote M. Biology and therapeutic applications of peroxisome proliferator-activated receptors. Curr Topics Med Chem. 2012;12:548–84.CrossRefGoogle Scholar
  24. Michalik L, Desvergne B, Wahli W. Peroxisome-proliferator activated receptors and cancers: complex stories. Nat Rev Cancer. 2004;4(1):61–70.PubMedCrossRefGoogle Scholar
  25. Mitro N, Godio C, Crestani M. Fluorescence resonance energy transfer techniques to study ligand-mediated interactions of PPARs with coregulators. Methods Mol Biol. 2013;952:219–27.PubMedCrossRefGoogle Scholar
  26. Neels JG, Grimaldi PA. Physiological functions of peroxisome proliferator-activated receptor β. Physiol Rev. 2014;94:795–858.PubMedCrossRefGoogle Scholar
  27. Ravingerova T, Adameova A, Carnicka S, Nemcekova M, Kelly T, Matejikova J, Galatou E, Barlaka E, Lazou A. The role of PPAR in myocardial response to ischemia in normal and diseased heart. Gen Physiol Biophys. 2011;30:329–41.PubMedCrossRefGoogle Scholar
  28. Salam NK, Huang TH, Kota BP, Kim MS, Li Y, Hibbs DE. Novel PPAR-gamma agonists identified from a natural product library: a virtual screening, induced-fit docking and biological assay study. Chem Biol Drug Des. 2008;71:57–70.PubMedCrossRefGoogle Scholar
  29. Theocharis S, Margeli A, Vielh P, Kouraklis G. Peroxisome proliferator-activated receptor-gamma ligands as cell-cycle modulators. Cancer Treat Rev. 2004;30:545–54.PubMedCrossRefGoogle Scholar
  30. van Bilsen M, van Nieuwenhoven FA. PPARs as therapeutic targets in cardiovascular disease. Exp Opin Ther Targets. 2010;14(10):1029–45.CrossRefGoogle Scholar
  31. Xu HE, Lambert MH, Montana VG, et al. Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proc Natl Acad Sci USA. 2001;98:13919–24.PubMedPubMedCentralCrossRefGoogle Scholar
  32. Zoete V, Grosdidier A, Michielin O. Peroxisome proliferator-activated receptor structures: ligand specificity, molecular switch and interactions with regulators. Biochim Biophys Acta. 2007;1771:915–25.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.School of BiologyAristotle University of ThessalonikiThessalonikiGreece