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Journal of Lipid Research, Vol. 45, 543-550, March 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Cholesteryl ester transfer protein modulates the effect of liver X receptor agonists on cholesterol transport and excretion in the mouse

David Masson^1,2,*, Bart Staels^1,, Thomas Gautier^*, Catherine Desrumaux^*, Anne Athias^*, Naig Le Guern^*, Martina Schneider^*, Zoulika Zak^*, Laure Dumont^*, Valérie Deckert^*, Alan Tall, Xian-Cheng Jiang^** and Laurent Lagrost^*

^* Institut National de la Santé et de la Recherche Médicale U498, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France
Institut National de la Santé et de la Recherche Médicale U545, Département d'Athérosclérose, Institut Pasteur de Lille, BP245, 59019 Lille Cedex, France
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, NY 10032
^** State University of New York, Downstate Medical Center, Brooklyn, NY 11203

² To whom correspondence should be addressed. e-mail: david.masson{at}chu-dijon.fr

Human plasma, unlike mouse plasma, contains the cholesteryl ester transfer protein (CETP) that may influence the reverse cholesterol transport. Liver X receptor (LXR), an oxysterol-activated nuclear receptor induces CETP transcription via a direct repeat 4 element in the CETP gene promoter. The aim of the study was to assess in vivo the impact of LXR activation on CETP expression and its consequences on plasma lipid metabolism and hepatic and bile lipid content. Wild-type and humanized mice expressing CETP were treated for five days with T0901317 LXR agonist. This treatment produced marked rises in both hepatic CETP mRNA and plasma CETP activity levels. Interestingly, the LXR agonist-mediated, 2-fold rise in both total and HDL cholesterol levels in treated wild-type mice was not observed in CETPTg mice, and the accumulation of cholesterol in the liver of CETPTg mice was reversed by LXR agonist treatment. Moreover, LXR activation induced a 2-fold increase in hepatic LDL-receptor expression in wild-type and CETPTg mice, and it produced a significantly greater rise in biliary cholesterol concentration in CETPTg mice as compared with wild-type mice.

In conclusion, induction of CETP constitutes a major determinant of the effect of LXR agonists on cholesterol transport and excretion.

Abbreviations: CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; LXR, liver X receptor; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SREBP, sterol-responsive element binding protein

Supplementary key words bile • cholesterol • low density lipoprotein receptor • reverse cholesterol transport • transgenic mice

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