PPAR beta/delta Activation prevents hypertriglyceridemia caused by a high fat diet. Involvement of AMPK and PGC-1 alpha-Lipin 1-PPAR alpha pathway

Introduction: Excessive consume of hypercaloric and high in saturated fat food causes an atherogenic dyslipidemia. In this study we analyzed the effects of PPAR beta/delta activator GW501516 on the hypertriglyceridemia induced by a high-fat diet. Methods: Male mice were randomized in three groups: control (standard chow), high fat diet (HFD, 35% fat by weight, 58% Kcal from fat) and high fat diet plus GW501516 (3 mg/Kg/day). Treatment duration was three weeks. Results: HFD-induced hypertriglyceridemia was accompanied by a reduction in hepatic levels of phospho-AMPK and in PGC-1 alpha and Lipin 1 mRNA levels. All these effects were reversed by GW501516 treatment. The lack of changes in phospho-AMPK levels after GW501516 treatment in HFD-fed animals could be the result of an increase in the AMP/ATP ratio. GW501516 treatment also increased Lipin 1 protein levels in the nucleus, led to the amplification of the PGC-1 alpha-PPAR alpha pathway and increased PPAR alpha DNA-binding activity, as well as the expression of PPAR alpha-target genes involved in fatty acid oxidation. GW501516 also increased beta-hydroxibutirate plasmatic levels, a hepatic beta-oxidation end product. Finally, GW501516 increased the hepatic levels of the PPAR alpha endogenous ligand 16:0/18:1-PC and the expression of the VLDL receptor. Conclusion: These data indicate that the hypotriglyceridemic effect of GW501516 in mice subjected to HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1 alpha-Lipin 1-PPAR alpha pathway. (C) 2012 Elsevier Espana, S.L. and SEA. All rights reserved.