1. Introduction

3,4, Ppard through constructs targeting exon 4, which codes for the DNA binding domain, leads to embryonic lethality or impaired growth, which indicates that PPAR-δ plays a fundamental role in embryo development [ Peroxisome proliferator-activated receptor-delta (PPAR-δ, also known as PPAR-β) is a member of the PPAR subgroup in the nuclear receptor superfamily. PPARs act as ligand-activated transcription factors that regulate important cellular metabolic functions [ 1 ]. Although PPAR-δ is ubiquitously expressed, its expression level in different tissues varies depending on cell type and disease status [ 2 5 ]. Homozygous knockout of murinethrough constructs targeting exon 4, which codes for the DNA binding domain, leads to embryonic lethality or impaired growth, which indicates that PPAR-δ plays a fundamental role in embryo development [ 6 7 ].

2 , 13 S -hydroxyoctadecadienoic acid (13 S -HODE), and 15 S -hydroxyeicosatetraenoic acid (15 S -HETE)) [10,11, Details of PPAR structure and signaling mechanisms have been reviewed in detail in Reference [ 8 ] and will only be discussed briefly here. The characteristics of PPAR ligand-binding domains (LBD) allow for interaction of a broad range of potential ligands, including many lipid and lipid-like molecules [ 8 ]. Natural ligands for PPAR-δ include polyunsaturated fatty acids (PUFA, e.g., arachidonic and linoleic acid)) and their metabolites (e.g., prostacyclin/PGI, 13-hydroxyoctadecadienoic acid (13-HODE), and 15-hydroxyeicosatetraenoic acid (15-HETE)) [ 9 12 ]. Although PPAR-δ has a narrower LBD relative to PPARs-α and-γ, binding pocket characteristics allow potential interaction with a variety of ligands, albeit many appear to bind at relatively low affinities [ 13 ]. While many potential endogenous ligands have been suggested in the literature, there is still some uncertainty about the physiological significance [ 14 ]. Selective ligands targeting PPAR-δ have also been developed, although none have been approved for clinical use to date [ 14 15 ].

20, PPAR signaling can be regulated in multiple ways, with outcomes depending upon whether PPAR and its binding partners are bound by ligand or not, ligand type (agonist, antagonist, partial agonist, etc.), and concentration as well as the availability of various coactivators or repressors [ 8 ]. The delivery of natural PPAR-δ ligands is facilitated by fatty acid transport proteins (FATPs) and fatty acid translocase (FAT, also known as CD36), which aid in import of extracellular lipids into the cell [ 16 17 ] and fatty-acid-binding proteins (FABPs), which transport cytoplasmic lipids within the cell [ 18 19 ]. Although most FABPs can bind a number of different lipids, it is unknown whether there is any selectivity in terms of the ligands FABP shuttles to PPARs [ 18 21 ]. In relation to PPAR-δ, FABP5 (also known as K-FABP or E-FABP) appears to be important for transport of lipid ligands to the nucleus [ 22 ]. Interestingly, FABP5 expression largely parallels that of PPAR-δ, and interaction between the two appears to be important in both normal and disease states, including many cancers [ 19 ]. Although a more detailed discussion is beyond the scope of this review, the interrelationship between the PPARs, their endogenous ligands, and various lipid transport proteins is complex, and several of these transport proteins are known transcriptional targets of PPARs (reviewed in References [ 16 19 ]).

23, Activation of PPARs by their ligands has been discussed in detail elsewhere and will be described only briefly here [ 8 24 ]. PPAR-δ activation requires interaction with various partners in the nucleus to transcriptionally regulate gene expression. Like other PPARs, PPAR-δ heterodimerizes with the retinoid X receptor (RXR) to activate or repress expression of downstream target genes by binding to PPAR response elements (PPREs) in their promoters [ 25 26 ]. In the absence of ligand binding, PPAR-RXR complexes are associated with corepressive factors and histone deacetylases that prevent transcriptional activation. Binding of an activating ligand to PPAR-δ leads to conformational changes that release corepressors and allow binding of coactivators [ 8 27 ]. In addition, PPARs can also engage in transrepression of other transcription factors. For example, in its unliganded state, PPAR-δ has been shown to form a complex with the transcription factor BCL-6, which prevents BCL-6 from repressing proinflammatory cytokine genes; therefore, this interaction promotes inflammation [ 28 29 ]. Conversely, binding of PPAR-δ agonist leads to disruption of the complex, and BCL-6 is freed to repress gene expression [ 28 ]. PPAR-δ has also been reported to interact with other transcription factors, such as β-catenin or NF-κB, to regulate gene expression [ 30 31 ].

Accumulating evidence has demonstrated that PPAR-δ can have distinct roles depending on the context (e.g., healthy vs. diseased, specific type of disease). While PPAR-δ allows normal cells (e.g., muscle cells and pancreatic cells) to better cope with adverse nutrient and energy pressures, PPAR-δ overexpression or hyperactivation can lead to promotion of inflammation and tumorigenesis. We will address some of the known discrepancies concerning PPAR-δ’s putative roles in metabolism, inflammation, and cancer in this review.