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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2006;26:2316.)
© 2006 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

FXR Deficiency Causes Reduced Atherosclerosis in Ldlr^–/– Mice

Yanqiao Zhang; Xuping Wang; Charisse Vales; Florence Ying Lee; Hans Lee; Aldons J. Lusis; Peter A. Edwards

From the Departments of Biological Chemistry (Y.Z., F.Y.L., H.L., P.A.E.), Medicine (Y.Z., X.W., C.V., A.J.L and P.A.E.), and Human Genetics (A.J.L.), David Geffen School of Medicine, and the Molecular Biology Institute (A.J.L., P.A.E.), University of California at Los Angeles, Calif.

Correspondence to Yanqiao Zhang, Department of Medicine, Division of Cardiology, CHS BH307, University of California, Los Angeles, 10833 Le Conte Ave, Los Angeles, CA 90095. E-mail yqzhang{at}mednet.ucla.edu

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.

Based on the observation that Fxr^–/– mice exhibit a proatherogenic lipoprotein profile, we investigated the role of FXR in the development of atherosclerosis. 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.

Key Words: atherosclerosis • cholesterol • FXR • LDLR • nuclear receptor

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