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Journal of Lipid Research, Vol. 46, 2356-2366, November 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Lack of stimulation of cholesteryl ester transfer protein by cholesterol in the presence of a high-fat diet

Sukhinder Kaur Cheema¹, Alka Agarwal-Mawal, Cathy M. Murray and Stephanie Tucker

Department of Biochemistry, Memorial University of Newfoundland, St. John's, Newfoundland A1B 3X9, Canada

Published, JLR Papers in Press, August 16, 2005. DOI 10.1194/jlr.M500051-JLR200

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

Cholesteryl ester transfer protein (CETP) is a key protein involved in the reverse cholesterol transport pathway. The regulation of CETP by dietary fats is not clearly understood. Transgenic mice expressing human CETP under the control of its natural flanking region were fed low- or high-fat diets enriched in monounsaturated fatty acids (MUFAs) or saturated fatty acids in the presence or absence of cholesterol. Addition of cholesterol to the low-fat MUFA diet increased CETP activity and mRNA expression, whereas addition of cholesterol to the high-fat MUFA diet led to a decrease in CETP activity and mRNA expression. In SW 872 cells, oleic acid and cholesterol stimulated CETP gene expression when given alone. However, addition of fatty acids along with cholesterol interfered with the stimulatory effect of cholesterol on CETP gene regulation. Cholesterol-mediated stimulation of CETP involves the transcription factor liver X receptor (LXR). High-fat MUFA diets inhibited the expression of LXR, and addition of cholesterol to the high-fat MUFA diet did not rescue LXR expression.

Therefore, we present evidence for the first time that inhibition of LXR expression by a high-fat MUFA diet leads to inhibition of CETP stimulation by cholesterol.

Abbreviations: CAT, chloramphenicol acetyl transferase; CETP, cholesteryl ester transfer protein; CETP-TG, transgenic mice expressing human cholesteryl ester transfer protein; cyp7, cholesterol 7- hydroxylase; LXR, liver X receptor; LXRE, liver X receptor response element; PPAR, peroxisome proliferator-activated receptor; PPRE, peroxisome proliferator response element; RXR, retinoid X receptor; SFA, saturated fatty acid

Supplementary key words transgenic mice • dietary fat and cholesterol • liver X receptor • peroxisome proliferator-activated receptor

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