ω-6 lipids regulate PPAR turnover via reciprocal switch between PGC-1 alpha and ubiquitination

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.

Methods and 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.

Conclusion: 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.