RGD Reference Report - Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells. - Rat Genome Database

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Atorvastatin prevents peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) downregulation in lipopolysaccharide-stimulated H9c2 cells.

Authors: Planavila, A  Sanchez, RM  Merlos, M  Laguna, JC  Vazquez-Carrera, M 
Citation: Planavila A, etal., Biochim Biophys Acta. 2005 Sep 15;1736(2):120-7.
RGD ID: 1601466
Pubmed: PMID:16139565   (View Abstract at PubMed)
DOI: DOI:10.1016/j.bbalip.2005.08.001   (Journal Full-text)

Although abnormalities in cardiac fatty acid metabolism are involved in the development of several cardiac pathologies, the mechanisms underlying these changes are not well understood. Given the prominent role played by peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta in cardiac fatty acid metabolism, the aim of this study was to examine the effects of nuclear factor (NF)-kappaB activation on the activity of this nuclear receptor. Embryonic rat heart-derived H9c2 cells stimulated with lipopolysaccharide (LPS) showed a reduction (38%, P<0.05) in the mRNA levels of the PPARbeta/delta-target gene pyruvatedehydrogenase kinase 4 (PDK4) that was prevented in the presence of the NF-kappaB inhibitors parthenolide (10 microM) and atorvastatin (10 microM). Electrophoretic mobility shift assay revealed that both parthenolide and atorvastatin significantly decreased LPS-stimulated NF-kappaB binding activity in H9c2 cardiac cells. LPS-stimulation of H9c2 cardiac cells also led to a 30% reduction (P<0.05) in the mRNA levels of PPARgamma Coactivator 1 (PGC-1) that was consistent with the reduction in the protein levels of this coactivator. In the presence of either atorvastatin or parthenolide, the reduction in PGC-1 expression was prevented. Co-immunoprecipitation studies showed that LPS-stimulation led to a reduction in the physical interaction between PGC-1 and PPARbeta/delta and that this reduction was prevented in the presence of atorvastatin. Finally, electrophoretic mobility shift assay revealed that parthenolide and atorvastatin prevented LPS-mediated reduction in PPARbeta/delta binding activity in H9c2 cardiac cells. These results suggest that LPS-mediated NF-kappaB activation inhibits the expression of genes involved in fatty acid metabolism by a mechanism involving reduced expression of PGC-1, which in turn affects the PPARbeta/delta transactivation of target genes involved in cardiac fatty acid oxidation.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
positive regulation of DNA-templated transcription  IMP 1601466 RGD 
positive regulation of fatty acid oxidation  IMP 1601466 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Ppargc1a  (PPARG coactivator 1 alpha)


Additional Information