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  • Title: FXR deficiency causes reduced atherosclerosis in Ldlr-/- mice.
    Author: Zhang Y, Wang X, Vales C, Lee FY, Lee H, Lusis AJ, Edwards PA.
    Journal: Arterioscler Thromb Vasc Biol; 2006 Oct; 26(10):2316-21. PubMed ID: 16825595.
    Abstract:
    OBJECTIVE: Based on the observation that Fxr-/- mice exhibit a proatherogenic lipoprotein profile, we investigated the role of FXR in the development of atherosclerosis. METHODS AND RESULTS: Administration of a western diet to Fxr-/- mice or wild-type mice does not result in the development of significant atherosclerotic lesions. Consequently we generated Fxr-/- Ldlr-/- (DKO) mice and compared lesion development with Ldlr-/- mice. After 16 weeks on a Western diet, en face analysis of the aorta indicated that the male DKO mice had reduced atherosclerotic lesions as compared with Ldlr-/- mice. Plasma low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were reduced by 40% to 50%, whereas triglyceride levels increased 4-fold in the male DKO mice. Finally, peritoneal macrophages freshly isolated from male DKO mice had reduced expression of CD36 mRNA and decreased neutral lipid accumulation, as compared with Ldlr-/- mice. CONCLUSIONS: FXR deficiency in male, but not female, Ldlr-/- mice results in a reduction in the size of atherosclerotic lesions in the aorta. The reduction in atherosclerosis may result from a decrease in plasma low-density lipoprotein cholesterol, coupled with reduced expression of CD36 in macrophages of DKO mice.
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