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J. Biol. Chem., Vol. 278, Issue 49, 49072-49078, December 5, 2003

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Enlargement of High Density Lipoprotein in Mice via Liver X Receptor Activation Requires Apolipoprotein E and Is Abolished by Cholesteryl Ester Transfer Protein Expression^*

Xian-Cheng Jiang¶, Thomas P. Beyer, Zhiqiang Li, Jin Liu, Wei Quan, Robert J. Schmidt, Youyan Zhang, William R. Bensch, Patrick I. Eacho, and Guoqing Cao||

From the Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285 and the Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, New York 11203

The factors involved in the generation of larger high density lipoprotein (HDL) particles, HDL₁ and HDL_c, are still not well understood. Administration of a specific synthetic liver X receptor (LXR) agonist, T0901317, in mice resulted in an increase of not only HDL cholesterol but also HDL particle size (Cao, G., Beyer, T. P., Yang, X. P., Schmidt, R. J., Zhang, Y., Bensch, W. R., Kauffman, R. F., Gao, H., Ryan, T. P., Liang, Y., Eacho, P. I., and Jiang, X. C. (2002) J. Biol. Chem. 277, 39561–39565). We have investigated the roles that apoE and CETP may play in this process. We treated apoE-deficient, cholesterol ester transport protein (CETP) transgenic, and wild type mice with various doses of the LXR agonist and monitored their HDL levels. Fast protein liquid chromatography and apolipoprotein analysis revealed that in apoE knockout mouse plasma, there was neither induction of larger HDL formation nor increase of HDL cholesterol, suggesting that apoE is essential for the LXR agonist effects on HDL metabolism. In CETP transgenic mice, CETP expression completely abolished LXR agonist-mediated HDL enlargement and greatly attenuated HDL cholesterol levels. Analysis of HDL particles by electron microscope and nondenaturing gel electrophoresis revealed similar findings. In apoE-deficient mice, LXR agonist also produced a significant increase in very low density lipoprotein/low density lipoprotein cholesterol and apolipoprotein B content. Our studies provide direct evidence that apoE and CETP are intimately involved in the accumulation of the enlarged HDL (HDL₁ or HDL_c) particles in mice.

Received for publication, April 23, 2003 , and in revised form, August 22, 2003.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

These two authors contributed equally to this work.

^¶ Supported by National Institute of Health Grants HL-69817 and HL-64735. To whom correspondence may be addressed. Tel.: 718-270-6701; Fax: 718-270-3732; E-mail: xjiang{at}downstate.edu. || To whom correspondence may be addressed. Tel.: 317-433-3535; Fax: 317-276-1417; E-mail: Guoqing_Cao{at}lilly.com.

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