**8. Acknowledgments**

226 Dyslipidemia - From Prevention to Treatment

product of acetyl-CoA carboxylase, which, in turn, is inhibited by AMPK. This kinase is a metabolic sensor that detects low ATP levels and increases oxidative metabolism (Reznick & Shulman, 2006), by reducing the levels of malonyl-CoA. Interestingly, activation of fatty acid oxidation by overexpressing CPT-1 in cultured skeletal muscle cells (Sebastian et al., 2007) and in mouse skeletal muscle (Bruce et al., 2009) improves lipid-induced insulin resistance. Hence, this approach may provide a valid therapeutic strategy to prevent this pathology. Activation of PPARβ/δ by its ligands (including GW501516) enhances fatty acid catabolism in adipose tissue and skeletal muscle, thereby delaying weight gain (for a review see (Barish et al., 2006)). This increase in fatty acid oxidation in human skeletal muscle cells following PPARβ/δ activation by GW501516 is dependent on both PPARβ/δ and AMPK (Kramer et al., 2007). AMPK is activated by GW501516 by modulating the ATP:AMP ratio (Kramer et al., 2007). Despite these data, little information was available on whether the increase in fatty acid oxidation attained after PPARβ/δ activation prevented fatty acid-induced inflammation and insulin resistance in skeletal muscle cells. However, we have recently reported that the PPARβ/δ ligand GW501516 prevented palmitate-induced inflammation and insulin resistance in skeletal muscle cells (Coll et al., 2010b). Treatment with GW501516 enhanced the expression of two-well known PPARβ/δ-target genes involved in fatty acid oxidation, CPT-1 and pyruvate dehydrogenase kinase 4 (PDK-4), and increased the phosphorylation of AMPK. This prevented the reduction in fatty acid oxidation caused by palmitate exposure. In agreement with these changes, GW501516 treatment reversed the increase in DAG and PKCθ activation caused by palmitate. These effects were abolished in the presence of the CPT-1 inhibitor etomoxir, thereby implicating increased fatty acid oxidation in the changes. Consistent with these findings, PPARβ/δ activation by GW501516 blocked palmitate-induced NF-κB DNA-binding activity. Likewise, drug treatment inhibited the increase in IL-6 expression caused by palmitate in C2C12 myotubes and human skeletal muscle cells, as well as the protein secretion of this cytokine. Overall, these findings indicate that PPARβ/δ attenuates fatty acid-induced NF-κB activation and the subsequent development of insulin resistance in skeletal muscle cells by reducing DAG accumulation. Interestingly, it has been suggested that the hypotrigliceridemic effect of GW501516 in humans is dependent of the increase in CPT-1 expression observed in skeletal muscle

Reduction of LDL-C, the main target of hypolipidemic therapy, has been proved effective reducing morbidity and mortality associated to CVD. However, a high proportion of patients receiving statins, the most lipid-lowering family of drugs used, do not reach optimal LDL-C levels. In addition, even in those patients reaching the optimal LDL-C levels following statin treatment, a residual risk remains, probably due to the presence of other risk factors, including the presence of atherogic dyslipidemia (described by the presence of high triglycerides, low HDL-C levels, and the presence of small dense LDL particles), glucose metabolism alterations and additional non-lipid-related risk factors. Several studies have confirmed that PPARβ/δ plays an important role in the regulation of lipoprotein metabolism, leading to reductions in the levels of plasma triglycerides and LDL-C and increases in HDL-C in different animal models. Taken together, these effects attained following PPARβ/δ activation on lipoprotein metabolism are so promising that this nuclear

(Riserus et al., 2008).

**7. Conclusion** 

The author's work that is summarized in this review was supported by grants from the Ministerio de Ciencia e Innovación of Spain (SAF2009-06939). CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) is an Instituto de Salud Carlos III project. L.S-M. and L.S. were supported by FPI grants from the Spanish Ministerio de Ciencia e Innovación. We would like to thank the University of Barcelona's Language Advisory Service for its help.
