The PPARß/d activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1a-Lipin 1-PPARa pathway leading to increased fatty acid oxidation

Autor: Barroso E, Rodríguez-Calvo R, Serrano-Marco L, Astudillo AM, Balsinde J, Palomer FX, Vazquez M
Rok vydání: 2011
Zdroj: Endocrinology
r-FSJD: Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
Fundació Sant Joan de Déu
r-FSJD. Repositorio Institucional de Producción Científica de la Fundació Sant Joan de Déu
instname
ISSN: 0013-7227
Popis: Metabolic syndrome-associated dyslipidemia is mainly initiated by hepatic overproduction of the plasma lipoproteins carrying triglycerides. Here we examined the effects of the peroxisome proliferator-activated receptors (PPAR)-ß/d activator GW501516 on high-fat diet (HFD)-induced hypertriglyceridemia and hepatic fatty acid oxidation. Exposure to the HFD caused hypertriglyceridemia that was accompanied by reduced hepatic mRNA levels of PPAR-? coactivator 1 (PGC-1)-a and lipin 1, and these effects were prevented by GW501516 treatment. GW501516 treatment also increased nuclear lipin 1 protein levels, leading to amplification in the PGC-1a-PPARa signaling system, as demonstrated by the increase in PPARa levels and PPARa-DNA binding activity and the increased expression of PPARa-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma ß-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPARa, 16:0/18:1-phosphatidilcholine and markedly enhanced the expression of the hepatic Vldl receptor. Interestingly, GW501516 prevented the reduction in AMP-activated protein kinase (AMPK) phosphorylation and the increase in phosphorylated levels of ERK1/2 caused by HFD. In addition, our data indicate that the activation of AMPK after GW501516 treatment in mice fed HFD might be the result of an increase in the AMP to ATP ratio in hepatocytes. These findings indicate that the hypotriglyceridemic effect of GW501516 in HFD-fed mice is accompanied by an increase in phospho-AMPK levels and the amplification of the PGC-1a-lipin 1-PPARa pathway.
Databáze: OpenAIRE
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