**4. PPARβ/δ-specific features and ligands**

The crystal structure of the ligand-binding domain of the PPARβ/δ isotype, which was first cloned in *Xenopus laevis* (Dreyer et al., 1992), revealed an exceptionally large pocket of approximately 1300 Å3. This pocket is similar to that of PPARγ, but much larger than the pockets of other nuclear receptors (Takada et al., 2000; Xu et al., 1999), which may explain, at least in part, the great variety of natural and synthetic ligands that bind to and activate this nuclear receptor. Saturated (14 to 18 carbons) and polyunsaturated (20 carbons in

The PPAR family consists of three members, PPARα (NR1C1 according to the unified nomenclature system for the nuclear receptor superfamily), PPARβ/δ (NR1C2) and PPARγ (NR1C3) (Auwerx et al., 1999). PPARα was the first PPAR to be identified and is the molecular target of the fibrate hypolipidemic class of drugs. This PPAR isotype is expressed primarily in tissues with a high level of fatty acid catabolism such as liver, brown fat, kidney, heart and skeletal muscle (Braissant et al., 1996). PPARγ has a restricted pattern of expression, mainly in white and brown adipose tissues and macrophages, whereas other tissues such as skeletal muscle and heart contain limited amounts. The γ isotype is the molecular target for the anti-diabetic drugs, thiazolidinediones. PPARβ/δ is ubiquitously expressed and, for this reason, was initially thought to be a "housekeeping gene" (Kliewer et al., 1994). However, studies with knockout mice (Barak et al., 2002; Peters et al., 2000; Tan et al., 2001) and the development of specific and high-affinity ligands for this receptor have shown that PPARβ/δ is a potential molecular target for prevention or treatment of several disorders. In this review we will highlight the role of PPARβ/δ in those metabolic processes

Fig. 1. Molecular mechanisms of Peroxisome Proliferator-Activated Receptors (PPARs). PPARs are ligand-activated transcription factors that regulate gene expression through two

The crystal structure of the ligand-binding domain of the PPARβ/δ isotype, which was first cloned in *Xenopus laevis* (Dreyer et al., 1992), revealed an exceptionally large pocket of approximately 1300 Å3. This pocket is similar to that of PPARγ, but much larger than the pockets of other nuclear receptors (Takada et al., 2000; Xu et al., 1999), which may explain, at least in part, the great variety of natural and synthetic ligands that bind to and activate this nuclear receptor. Saturated (14 to 18 carbons) and polyunsaturated (20 carbons in

mechanisms: transactivation and transrepression. In transactivation PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator-response elements (PPREs), which are located in the promoter regions of genes involved in glucose and fatty acid metabolism. PPARs may also regulate gene expression through a DNAindependent mechanism called transrepression. Through this mechanism, PPARs inhibit the activity of several transcription factors such as NF-κB, which leads to anti-inflammatory

effects. STAT denotes signal transducers and activators of transcription.

**4. PPARβ/δ-specific features and ligands** 

with potential for treating dyslipidemia.

length) fatty acids have affinities for PPARβ/δ in the low micromolar range (Xu et al., 1999; Forman et al., 1997; Yu et al., 1995; Krey et al., 1997). In addition, all-trans-retinoic acid (vitamin A) (Shaw et al., 2003) and fatty acids derived from VLDL (Chawla et al., 2003) can activate PPARβ/δFinally, the availability of three synthetic ligands (GW501516, GW0742 and L-165041) that activate PPARβ/δ at very low concentrations both in vivo and in vitro with high selectivity over other PPAR isotypes (Sznaidman et al., 2003) led to a huge increase in experimental studies on the role of PPARβ/δ in cellular processes. The EC50 for these compounds assessed with recombinant human PPARβ/δ were 1.0 nM for GW0742, 1.1 nM for GW501516 and 50 nM for L-165041 (Berger et al., 1999; Sznaidman et al., 2003).
