**2. Hypertriglyceridemia is crucial in the pathogenesis of atherogenic dyslipidemia**

It is now recognized that the atherogenic dyslipidemia is mainly initiated by the hepatic overproduction of the plasma lipoproteins carrying triglycerides, the VLDL, which induce a sequence of lipoprotein changes leading to atherogenic lipid abnormalities in type 2 diabetes mellitus and metabolic syndrome (Adiels et al., 2008). Under these pathological conditions, the presence of insulin resistance at the level of adipose tissue leads to enhanced lypolisis and reduced free fatty acid (FFA) uptake and esterification which results in increased flux into the liver of FFA, which are either oxidized or esterified for triglyceride production, leading to hepatic steatosis and oversecretion into plasma of larger triglyceriderich VLDL particles (Chan & Watts, 2011). These particles compete with chylomicrons and its remnants for clearance pathways regulated by lipoprotein lipase, an endothelial-bound enzyme, and by hepatic receptors, thereby exacerbating postprandial dyslipidemia. In addition, insulin resistance increases hepatic secretion of apoC-III, which is attached to VLDL delaying the catabolism of TRLs by inhibiting lipoprotein lipase and binding of remnant TRLs to hepatic clearance receptors (Chan & Watts, 2011). Finally, expansion of the VLDL triglyceride pool leads to cholesterol depletion and triglyceride enrichment of LDL and HDL through cholesteryl ester transfer protein, which facilitates the movement of cholesterol esters to VLDL, intermediate-density lipoprotein (IDL) and LDL from cholesterol ester rich HDL, leading to the accumulation in plasma of small, dense LDLs and a reduction in HDLs (Taskinen, 2003).

Since residual risk remains even after achieving an optimal LDL-C concentration with statins (Barter et al., 2007), probably due to other risk factors, such as high triglycerides, low HDL-C levels, defective glucose metabolism and other non-lipid-related risk factors (Kannel, 1983; Castelli, 1992; Lorenzo et al., 2010; Cederberg et al., 2010), the development of new drugs aimed at improving risk reduction is necessary. Among the new drugs for the treatment of the risk factors leading to the residual risk, PPARβ/δ activators might have a promising future. Interestingly, PPARβ/δ agonists have been demonstrated to be effective raising HDL-C and lowering triglyceride concentrations (Kersten, 2008). In addition to their lipid-modifying properties, PPARβ/δ agonists improve insulin resistance, which may also confer protection against the development of dyslipidemia (Coll et al., 2010a). This review summarizes the effects of PPARβ/δ on dyslipidemia identified during the last few years.
