Abstract 13550: Peroxisome Proliferator-Activated Receptor γ Agonists Up-Regulate Stearoyl-Coa Desaturase 1 and Attenuate Palmitate-Induced Stress of Endoplasmic Reticulum
Background: Endoplasmic reticulum (ER) stress plays an important role in the progression of atherosclerosis and plaque vulnerability. Dietary saturated fatty acids (SFAs) promote the metabolic syndrome and atherosclerotic cardiovascular disease. SFAs are lipotoxic which in turn lead to ER stress and apoptosis in many types of cells. Clinical trials have shown that pioglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, reduces cardiovascular events in type 2 diabetes. However, the effects of PPARγ agonist on ER stress has not been determined. We examined the effect of PPARγ agonist on macrophage ER stress and apoptosis induced by palmitate, a most abundant SFA in the serum.
Results: Pioglitazone and rosiglitazone reduced palmitate-induced phosphorylation of PERK (47.9% vs.palmitate, p<0.05), a marker of ER stress, in RAW264.7 macrophage cells line and peritoneal macrophages of mice. Pioglitazone also suppressed palmitate-induced apoptosis (50.1% vs. palmitate, p<0.01) with inhibition of CHOP expression (44.1% vs. palmitate, p<0.01), JNK phosphorylation (65.1% vs palmitate, p<0.05) and cleavage of caspase3 (29.7% vs. palmitate, p<0.01). GW9662, a selective PPARγ antagonist, reversed these effects of pioglitazone (p<0.05 vs. pioglitazone +palmitate) indicating an essential role of PPARγ in this process. PPARγ agonists increased the mRNA level of stearoyl-CoA desaturase1 (SCD1) (302% vs. control, p<0.01) that introduces a double bond on the acyl chain of long-chainfatty acid. 4-(2-Chlorophenoxy)-N-(3-(3 methylcarbamoyl) phenyl) piperidine-1-carboxamide, an inhibitor of SCD1, abolished the anti-ER stress and anti-apoptotic effects of pioglitazone.
Conclusion: PPARγ agonists attenuate palmitate-induced macrophage ER stress and apoptosis through desaturation of saturated fatty acid and an increase in unsaturated fatty acid level. PPARγ agonists reduce cardiovascular events by up-regulating SCD-1 in macrophage.
- © 2012 by American Heart Association, Inc.