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Originally published In Press as doi:10.1194/jlr.M500390-JLR200 on September 26, 2005

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Journal of Lipid Research, Vol. 46, 2595-2604, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Loss of functional farnesoid X receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice

Elyisha A. Hanniman*, Gilles Lambert{dagger}, Tanya C. McCarthy* and Christopher J. Sinal1,*

* Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
{dagger} University of Nantes Medical School, Institut National de la Santé et de la Recherche Médicale U539, Nantes, France

Published, JLR Papers in Press, September 26, 2005. DOI 10.1194/jlr.M500390-JLR200

1 To whom correspondence should be addressed. e-mail: csinal{at}dal.ca

The farnesoid X receptor (FXR) is a bile acid-activated transcription factor that regulates the expression of genes critical for bile acid and lipid homeostasis. This study was undertaken to investigate the pathological consequences of the loss of FXR function on the risk and severity of atherosclerosis. For this purpose, FXR-deficient (FXR–/–) mice were crossed with apolipoprotein E-deficient (ApoE–/–) mice to generate FXR–/–ApoE–/– mice. Challenging these mice with a high-fat, high-cholesterol (HF/HC) diet resulted in reduced weight gain and decreased survival compared with wild-type, FXR–/–, and ApoE–/– mice. FXR–/–ApoE–/– mice also had the highest total plasma lipids and the most atherogenic lipoprotein profile. Livers from FXR–/– and FXR–/– ApoE–/– mice exhibited marked lipid accumulation, focal necrosis (accompanied by increased levels of plasma aspartate aminotransferase), and increased inflammatory gene expression. Measurement of en face lesion area of HF/HC-challenged mice revealed that although FXR–/– mice did not develop atherosclerosis, FXR–/–ApoE–/– mice had approximately double the lesion area compared with ApoE–/– mice.

In conclusion, loss of FXR function is associated with decreased survival, increased severity of defects in lipid metabolism, and more extensive aortic plaque formation in a mouse model of atherosclerotic disease.

Abbreviations: apoC-II, apolipoprotein C-II; AST, aspartate aminotransferase; FPLC, fast-performance liquid chromatography; FXR, farnesoid X receptor; H+E, hematoxylin and eosin; HF/HC, high-fat/high-cholesterol; MAC1, macrophage antigen 1; RCT, reverse cholesterol transport; TNF-{alpha}, tumor necrosis factor-{alpha}

Supplementary key words atherosclerosis • nuclear receptor • liver


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