| 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. | |
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MedLine Citation:
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PMID: 21363937 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Emma Barroso; Ricardo Rodríguez-Calvo; Lucía Serrano-Marco; Alma M Astudillo; Jesús Balsinde; Xavier Palomer; Manuel Vázquez-Carrera |
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Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2011-03-01 |
Journal Detail:
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Title: Endocrinology Volume: 152 ISSN: 1945-7170 ISO Abbreviation: Endocrinology Publication Date: 2011 May |
Date Detail:
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Created Date: 2011-04-22 Completed Date: 2011-07-22 Revised Date: 2012-01-10 |
Medline Journal Info:
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Nlm Unique ID: 0375040 Medline TA: Endocrinology Country: United States |
Other Details:
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Languages: eng Pagination: 1848-59 Citation Subset: AIM; IM |
Affiliation:
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Department of Pharmacology and Therapeutic Chemistry, and Institut de Biomedicina de la University of Barcelona, Barcelona. Spain. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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AMP-Activated Protein Kinases
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metabolism* Animals Dietary Fats / administration & dosage, adverse effects Down-Regulation / drug effects Fatty Acids / metabolism Glucose Tolerance Test Hypertriglyceridemia / etiology, metabolism, prevention & control Immunoblotting Lipids / blood Liver / drug effects*, metabolism Mice Nuclear Proteins / genetics*, metabolism Oxidation-Reduction / drug effects PPAR alpha / genetics*, metabolism PPAR gamma / agonists, metabolism PPAR-beta / agonists, metabolism Phosphorylation / drug effects Receptors, LDL / genetics, metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction / drug effects Thiazoles / pharmacology* Trans-Activators / genetics*, metabolism Triglycerides / metabolism |
| Chemical | |
Reg. No./Substance:
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0/Dietary Fats; 0/Fatty Acids; 0/GW 501516; 0/Lipids; 0/Nuclear Proteins; 0/PPAR alpha; 0/PPAR gamma; 0/PPAR-beta; 0/Ppargc1a protein, mouse; 0/Receptors, LDL; 0/Thiazoles; 0/Trans-Activators; 0/Triglycerides; 0/VLDL receptor; EC 2.7.11.1/AMP-Activated Protein Kinases; EC 3.1.3.4/Lpin1 protein, mouse |
| Comments/Corrections | |
Comment In:
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Endocrinology. 2011 May;152(5):1742-4
[PMID:
21511987
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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