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This version published online on May 6, 2004
Molecular Endocrinology, doi:10.1210/me.2003-0477
Molecular Endocrinology Vol. 0, No. 2004 200304771-
doi:10.1210/me.2003-0477
Copyright © 2004 by the Endocrine Society.
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Submitted on December 10, 2003
Accepted on April 28, 2004

Liver X Receptors Regulate Apolipoprotein AIV-Implications of the Anti-atherosclerotic Effect of LXR Agonists

Yu Liang, Xian-Cheng Jiang, Ruijie Liu, Guosheng Liang, Thomas P. Beyer, Hong Gao, Timothy P. Ryan, Shuyu Dan Li, Patrick I. Eacho, and Guoqing Cao*

Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana 46285; Department of Anatomy and Cell Biology, SUNY Downstate Medical Center, Brooklyn, NY 11203; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9046

* To whom correspondence should be addressed. E-mail: Guoqing Cao{at}lilly.com.

Liver X receptors regulate target genes that are critical in lipoprotein metabolism and atherosclerosis. Apolipoprotein AIV is an apolipoprotein that is associated with chylomicrons and high-density lipoproteins (HDL). Plasma ApoAIV level in humans is inversely correlated with coronary artery events and overexpression of ApoAIV in mice results in significant reduction in atherosclerosis. We report here that LXRs directly regulate apoAIV at the transcriptional level. Treatment of C57B6 mice with a synthetic LXR agonist, T0901317, resulted in significant increases in plasma apoAIV that was associated with HDL. Examination of both intestinal and liver apoAIV mRNA revealed specific increases in liver mRNA only. In a human heptoma HepG2 cell model, apoAIV mRNA was upregulated upon the treatment with either native or synthetic LXR agonists. Nuclear run-on study revealed a significant increase in the ApoAIV transcriptional rate upon LXR activation. Examination of the human apoAIV proximal promoter revealed a potential LXR response element that demonstrated binding with HepG2 nuclear extracts. Co-transfection studies in HepG2 cells indicated that this responsive element was functional in mediating the human ApoAIV gene response to LXR agonists. In addition, we identified a functional LXR responsive element at 3' end enhancer region of mouse ApoAIV gene. We conclude that ApoAIV is a direct target gene of LXRs that may contribute to the anti-atherogenic effect of LXR activation.

NURSA Molecule Pages Link:

Nuclear Receptors:   LXRβ  |  LXRα
Ligands:   22α-Hydroxycholesterol  |  T0901317  |  9-cis-Retinoic acid



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