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

Abstract

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)...