**Peroxisome Proliferator-Activated Receptor β/δ (PPAR β/δ) as a Potential Therapeutic Target for Dyslipidemia**

Emma Barroso, Lucía Serrano-Marco, Laia Salvadó, Xavier Palomer and Manuel Vázquez-Carrera *Department of Pharmacology and Therapeutic Chemistry, Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders(CIBERDEM)-Instituto de SaludCarlos III and IBUB, (Biomedicine Institute of the University of Barcelona), Faculty of Pharmacy, University of Barcelona, Barcelona, Spain* 

#### **1. Introduction**

214 Dyslipidemia - From Prevention to Treatment

Zu, L., He, J., Jiang, H., Xu, C., Pu, S., & Xu, G. (2009). Bacterial endotoxin stimulates adipose

*Biol. Chem.*, Vol.284, No.9, pp. 5915-5926, ISSN 0021-9285

lipolysis via toll-like receptor 4 and extracellular signal-regulated kinase pathway. *J* 

Dyslipidemia is a powerful predictor of cardiovascular disease in patients at high risk (Turner et al., 1998), such as type 2 diabetic patients. Lowering of LDL-C is the prime target for treatment (2002), but even with intensification of statin therapy, a substantial residual cardiovascular risk remains (Barter et al., 2007; Miller et al., 2008; Fruchart et al., 2008; Shepherd et al., 2006). This may partly be due to atherogenic dyslipidemia. This term is commonly used to describe a condition of abnormally elevated plasma triglycerides and low high-density lipoprotein cholesterol (HDL-C), irrespective of the levels of LDL-C (Grundy, 1995). In addition to these key components, increased levels of small, dense LDL-C particles are also present, which in conjunction with the former components conform the also called "lipid triad" (Shepherd et al., 2005). Other abnormalities include accumulation in plasma of triglyceride-rich lipoproteins (TLRs), including chylomicron and very-low-density lipoprotein (VLDL) remnants. This is reflected by elevated plasma concentrations of non-HDL-C and apolipoprotein B-100 (apoB). Postprandially, there is also accumulation in plasma of TLRs and their remnants, as well as qualitative alterations in LDL and HDL particles. Thus, hypertriglyceridemia is associated with a wide spectrum of atherogenic lipoproteins not measured routinely (Taskinen, 2003). The presence of this lipid plasma profile with high triglyceride and low HDL-C levels have been shown to increase the risk of cardiovascular events independent of conventional risk factors (Bansal et al., 2007; Barter et al., 2007; deGoma et al., 2008). In fact, guidelines recommend modifying high triglyceride and low HDL-C as secondary therapeutic targets to provide additional vascular protection (2002). The presence of atherogenic dyslipidemia is seen in almost all patients with triglycerides > 2.2 mmol/l and HDL-C < 1.0 mmol/l, virtually all of whom have type 2 diabetes or abdominal obesity and insulin resistance (Taskinen, 2003). Most of these alterations are also characteristic of metabolic syndrome, which is defined as the clustering

Peroxisome Proliferator-Activated

activator and co-repressor proteins, etc.).

activation of downstream transcription factors.

with PPARs.

Receptor β/δ (PPARβ/δ) as a Potential Therapeutic Target for Dyslipidemia 217

sequences have been characterized within the promoter regions of PPAR target genes. The binding occurs in such a way that PPAR is always oriented to the DNA's 5'-end, while RXR is to the 3'-end. In the absence of ligand, high-affinity complexes are formed between PPAR-RXR heterodimers and nuclear receptor co-repressor proteins, which block transcriptional activation by sequestering the heterodimer from the promoter. Binding of the ligand to PPAR induces a conformational change resulting in dissociation of co-repressor proteins, so that the PPAR-RXR heterodimer can then bind to PPREs. Moreover, once activated by the ligand, the heterodimer recruits co-activator proteins that promote the initiation of transcription (Feige et al., 2006). As a consequence of these changes in transcriptional activity, binding of ligands to the receptor results in changes in the expression level of mRNAs encoded by PPAR target genes. In a specific cellular context, the activity of PPARs regulating the transcription of their target genes depends on many factors (relative expression of the PPARs, the promoter context of the target gene, the presence of co-

Thus, the transcriptional activity of PPARs is modulated by co-activators and co-repressors (Feige et al., 2006). One of the best described PPAR co-activators is PPARγ coactivator 1 α (PGC-1α). Silencing mediator for retinoic and thyroid hormone receptor (SMRT) and the nuclear receptor co-repressor (NCoR) are co-repressors that interact with the PPARs in the absence of ligands (Zamir et al., 1997). Receptor-interacting protein 140 (RIP140), an important metabolic regulator, is another ligand-dependent co-repressor which interacts

Finally, PPAR activity is also regulated at the post-transcriptional level by phosphorylation,

However, the regulation of gene transcription by PPARs extends beyond their ability to trans-activate specific target genes in an agonist-dependent manner. PPARs also regulate gene expression independently of binding to PPREs. They cross-talk with other types of transcription factors and influence their function without binding to DNA, through a mechanism termed receptor-dependent trans-repression (Daynes & Jones, 2002). Most of the anti-inflammatory effects of PPARs are probably explained by this mechanism (Kamei et al., 1996; Li et al., 2000). Thus, through this DNA-binding independent mechanism, PPARs suppress the activities of several transcription factors, including nuclear factor κB (NF-κB), activator protein 1 (AP-1), signal transducers and activators of transcription (STATs) and nuclear factor of activated T cells (NFAT). There are three main trans-repression mechanisms by which ligand-activated PPAR-RXR complexes negatively regulate the activities of other transcription factors. First, trans-repression may result from competition for limiting amounts of shared co-activators. Under conditions in which the levels of specific co-activators are rate-limiting, activation of PPAR may suppress the activity of other transcription factors that use the same co-activators (Delerive et al., 1999; Delerive et al., 2002). In the second mechanism, activated PPAR-RXR heterodimers are believed to act through physical interaction with other transcription factors (for example AP-1, NF-κB, NFAT or STATs). This association prevents the transcription factor from binding to its response element and thereby inhibits its ability to induce gene transcription (Desreumaux et al., 2001). The third trans-repression mechanism relies on the ability of activated PPAR-RXR heterodimers to inhibit the phosphorylation and activation of certain members of the mitogen-activated protein kinase (MAPK) cascade (Johnson et al., 1997), preventing

ubiquitinylation, and sumoylation (for a detailed review see (Feige et al., 2006)).

of multiple metabolic abnormalities, including abdominal obesity, dyslipidemia (high serum triglycerides and low serum HDL-C levels), glucose intolerance and hypertension (Eckel et al., 2005; Grundy et al., 2005).
