Abstract 70: PPARdelta Agonist GW1516 Attenuates Diet-Induced Dyslipidemia, Insulin Resistance and Aortic Inflammation in Ldlr -/- Mice
| Autor: | Lazar Bojic, Dawn Telford, Brian Sutherland, Cynthia Sawyez, Jane Edwards, Murray Huff |
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| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Arteriosclerosis, Thrombosis, and Vascular Biology. 32 |
| ISSN: | 1524-4636 1079-5642 |
| DOI: | 10.1161/atvb.32.suppl_1.a70 |
| Popis: | Objective: The peroxisome proliferator-activated receptor (PPAR) delta has been implicated in systemic lipid homeostasis and inflammation. However, the role of PPARdelta agonists as anti-atherogenic agents remains unclear. In the present study, we used low-density lipoprotein receptor-null mice (Ldlr-/-) fed a high fat (HF) diet to test the hypothesis that a selective PPARdelta agonist corrects metabolic dysregulation and attenuates inflammation associated with atherosclerosis. Methods and Results: Ldlr -/- mice were fed chow or HF (42% fat, 0.2% cholesterol) for 4 weeks. Subsequently, the HF group was fed either HF or HF plus GW1516 (3mg/kg/d) for a further 8 weeks. Fasting plasma triglyceride, total cholesterol and free fatty acids were significantly decreased (-50%) by intervention with GW1516. In addition, GW1516 normalized fasting blood glucose and improved glucose and insulin tolerance. GW1516 also enhanced total energy expenditure compared to HF-fed mice. In the aorta, ER-stress markers CHOP and GRP78 were significantly elevated in HF-fed mice, which were markedly attenuated by GW1516-intervention. Aortae of HF-fed mice also showed marked elevations in the expression of proinflammatory cytokines including Ccl3, Il1beta, Icam1, Tnf, Il6 and Ccl2. Furthermore, HF-aortae, compared to chow, displayed reduced expression of the M2 macrophage marker arginase-1(Arg1). Intervention with GW1516 significantly attenuated aortic expression of all examined proinflammatory cytokines, and restored Arg1 expression. Enhanced MAPKerk signalling and decreased AKT/FoxO1 signalling are known to induce inflammatory cytokine expression in vitro. HF-feeding induced phosphorylation (p) of the MAP kinases ERK1/2 and p38 and dampened levels of pAKT and pFoxO1 in the aorta. In contrast, aortae of GW1516-treated animals displayed normalized levels of pERK1/2, p-p38, pAKT and pFoxO1. Conclusions: These studies demonstrate that PPARdelta activation ameliorates dyslipidemia and insulin resistance in HF-fed Ldlr -/- mice. Furthermore, PPARdelta activation inhibits aortic ER-stress as well as dysregulation of MAPK and AKT/FoxO1 signalling induced by HF-feeding, resulting in inhibition of the inflammatory response within the aorta. |
| Databáze: | OpenAIRE |
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