FXR deficiency causes reduced atherosclerosis in Ldlr-/- mice

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.