PPARα, but not PPARγ, activators decrease macrophage-laden atherosclerotic lesions in a nondiabetic mouse model of mixed dyslipidemia

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Abstract

OBJECTIVE: Peroxisome proliferator-activated receptor (PPAR) alpha and gamma are nuclear receptors that may modulate atherogenesis, not only by correcting metabolic disorders predisposing to atherosclerosis but also by directly acting at the level of the vascular wall. The accumulation of lipid-laden macrophages in the arterial wall is an early pivotal event participating in the initiation and promotion of atherosclerotic lesion formation. Because PPARalpha and gamma modulate macrophage gene expression and cellular function, it has been suggested that their ligands may modulate atherosclerosis development via direct effects on macrophages. In this report, we investigated the effect of a PPARalpha ligand (fenofibrate) and 2 PPARgamma ligands (rosiglitazone and pioglitazone) on atherogenesis in a dyslipidemic nondiabetic murine model that develops essentially macrophage-laden lesions. METHODS AND RESULTS: Mice were fed a Western diet supplemented or not with fenofibrate (100 mpk), rosiglitazone (10 mpk), or pioglitazone (40 mpk) for 10 weeks. Atherosclerotic lesions together with metabolic parameters were measured after treatment. Fenofibrate treatment significantly improved lipoprotein metabolism toward a less atherogenic phenotype but did not affect insulin sensitivity. Contrarily, rosiglitazone and pioglitazone improved glucose homeostasis, whereas they did not improve lipoprotein metabolism. Fenofibrate treatment significantly decreased the accumulation of lipids and macrophages in the aortic sinus. However, surprisingly, neither rosiglitazone nor pioglitazone had an effect on lesion lipid accumulation or macrophage content. CONCLUSIONS: These results indicate that in a dyslipidemic nondiabetic murine model, PPARalpha, but not PPARgamma, activators protect against macrophage foam cell formation.

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Hennuyer, N., Tailleux, A., Torpier, G., Mezdour, H., Fruchart, J. C., Staels, B., & Fiévet, C. (2005). PPARα, but not PPARγ, activators decrease macrophage-laden atherosclerotic lesions in a nondiabetic mouse model of mixed dyslipidemia. Arteriosclerosis, Thrombosis, and Vascular Biology, 25(9), 1897–1902. https://doi.org/10.1161/01.ATV.0000175756.56818.ee

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