title: The PPARβ/δ activator GW501516 prevents the down-regulation of AMPK caused by a high-fat diet in liver and amplifies the PGC-1α-Lipin 1-PPARα pathway leading to increased fatty acid oxidation.
abstract: 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)-β/δ 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-γ coactivator 1 (PGC-1)-α 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-1α-PPARα signaling system, as demonstrated by the increase in PPARα levels and PPARα-DNA binding activity and the increased expression of PPARα-target genes involved in fatty acid oxidation. These effects of GW501516 were accompanied by an increase in plasma β-hydroxybutyrate levels, demonstrating enhanced hepatic fatty acid oxidation. Moreover, GW501516 increased the levels of the hepatic endogenous ligand for PPARα, 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-1α-lipin 1-PPARα pathway.
authors.affiliation: Department of Pharmacology and Therapeutic Chemistry, and Institut de Biomedicina de la University of Barcelona, Barcelona. Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.forename: Lucía
authors.initials: L
authors.lastname: Serrano-Marco
authors.forename: Alma M
authors.initials: AM
authors.lastname: Astudillo
authors.forename: Jesús
authors.initials: J
authors.lastname: Balsinde
authors.forename: Xavier
authors.initials: X
authors.lastname: Palomer
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D015536:Down-Regulation / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D005951:Glucose Tolerance Test; D015228:Hypertriglyceridemia / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control; D015151:Immunoblotting; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D047493:PPAR alpha / Q000235:genetics* / Q000378:metabolism; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010711:Phosphatidate Phosphatase; D010766:Phosphorylation / Q000187:drug effects; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology*; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005227:Fatty Acids; C425931:GW 501516; D008055:Lipids; D009687:Nuclear Proteins; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011973:Receptors, LDL; D013844:Thiazoles; D015534:Trans-Activators; D014157:Transcription Factors; D014280:Triglycerides; C036053:VLDL receptor; D055372:AMP-Activated Protein Kinases; C418978:Lpin1 protein, mouse; D010711:Phosphatidate Phosphatase