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.


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.
Zhang
Yanqiao
Y
Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. yqzhang@mednet.ucla.edu
Wang
Xuping
X
Vales
Charisse
C
Lee
Florence Ying
FY
Lee
Hans
H
Lusis
Aldons J
AJ
Edwards
Peter A
PA
D000818:Animals; D050197:Atherosclerosis / Q000209:etiology / Q000473:pathology*; D018955:CD36 Antigens / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000172:deficiency*; D004041:Dietary Fats / Q000008:administration & dosage; D005260:Female; D050356:Lipid Metabolism; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood; D017737:Macrophages, Peritoneal / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency*; D011973:Receptors, LDL / Q000172:deficiency*; D012727:Sex Characteristics; D014157:Transcription Factors / Q000172:deficiency*; D000099150:Receptor, Farnesoid X-Activated
D018955:CD36 Antigens; D004268:DNA-Binding Proteins; D004041:Dietary Fats; D008055:Lipids; D008074:Lipoproteins; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated