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Papers In Press, published online ahead of print September 26, 2005
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Pharmacology Dept., Dalhousie University, Halifax, Nova Scotia B3H 1X5
Corresponding Author: 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. The present study was undertaken to investigate the pathological consequences of loss of FXR function on the risk and severity of atherosclerosis. For this purpose, 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 to wildtype, 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 amino transferase and increased inflammatory gene expression. Measurement of en face lesion area of HF/HC challenged mice revealed that while FXR–/– mice did not develop atherosclerosis, FXR–/–ApoE–/– mice had approximately double the lesion area compared to 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.
Revised on September 15, 2005
Accepted on September 26, 2005
Loss of functional farnesoid X-receptor increases atherosclerotic lesions in apolipoprotein E-deficient mice
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