title: ω-6 lipids regulate PPAR turnover via reciprocal switch between PGC-1 alpha and ubiquitination.
abstract: OBJECTIVE
  Dietary ω-6 lipids such as linoleic acid and its oxidized forms (13-HPODE OxLA) interact with peroxisome proliferator-activated receptors (PPARs) and elicit pro and anti-atherogenic effects in vascular cells. Ligand-dependent PPAR protein turnover is promoted by ubiquitination, but attenuated by binding to its co-activator, peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1α). The objective of our study was to investigate if the dual atherogenic effects of ω-6 lipids are due to its regulation of PPAR turnover.
  
  
  RESULTS
  In rat aortic smooth muscle cells (RASMCs), oxidized linoleic acid (OxLA) at 10-50 μM induced and stabilized PPARα protein at earlier time points (0-4 h) but suppressed it at 12 h. Conversely, it activated PPARγ protein turnover at a later time point (12 h). Pre-treatment with the proteasome inhibitor (MG132) prevented OxLA mediated loss of PPAR stability and transactivity. Co-immunoprecipitation studies indicated a ligand mediated time-dependent reciprocal exchange of PPAR interaction between ubiquitination and PGC-1α. This ω-6 lipid mediated time-dependent switch between PPAR degradation versus stability helped modulate the pro and anti-atherogenic effects of these dietary lipids.
  
  
  CONCLUSIONS
  Our findings provide insights into the dual pro and anti-atherogenic effects of dietary ω-6 lipids on vascular cells by the regulation of PPAR turnover.
authors.affiliation: Department of Pharmacology, Physiology and Toxicology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV 25755, USA.
authors.forename: Jia
authors.initials: J
authors.lastname: Fei
authors.forename: Carla
authors.initials: C
authors.lastname: Cook
authors.forename: Nalini
authors.initials: N
authors.lastname: Santanam
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D008024:Ligands; D019787:Linoleic Acid / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism*; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism*; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D012333:RNA, Messenger / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D051381:Rats; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection; D054875:Ubiquitination
chemical_list: D015853:Cysteine Proteinase Inhibitors; D007976:Leupeptins; D008024:Ligands; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C501429:Ppargc1a protein, rat; D061988:Proteasome Inhibitors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D019787:Linoleic Acid; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde