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A more recent version of this article appeared on November 1, 2004

Papers In Press, published online ahead of print August 1, 2004
J. Lipid Res., doi:10.1194/jlr.M400119-JLR200
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Submitted on March 26, 2004
Revised on July 9, 2004
Accepted on July 26, 2004

Tissue-specific autoregulation of the LXRalpha gene facilitates induction of apoE in mouse adipose tissue

Stine Marie Ulven, Knut Tomas Dalen, Jan-Ake Gustafsson, and Hilde I. Nebb

Department of Nutrition, University of Oslo, Oslo, Oslo 0316

Corresponding Author: s.m.ulven{at}basalmed.uio.no

The functions of the liver X receptors (LXRs) are not well documented in adipose tissue. We demonstrate here that expression of the LXRalpha gene is highly induced in vivo and in vitro in mouse and human adipocytes in the presence of the synthetic LXR agonist, T0901317. This auto-regulation is caused by an identified LXRE motif in the mouse LXRalpha promoter, which is conserved in the human LXRalpha promoter. Using different LXR deficient mice we demonstrate that the basal expression level of LXRalpha is increased in LXRbeta -/- mice, while the basal expression level of LXRbeta is unchanged in LXRalpha -/- mice. The two LXR isoforms can compensate for each other in mediating ligand activated regulation of LXR target genes involved in lipid homeostasis in adipose tissue. Sterol regulatory element binding protein (SREBP-1), ATP-binding cassette A1 (ABCA1), ABCG1 as well as apolipoprotein E (apoE) are induced in vivo by T0901317 in wild-type mice, LXRalpha -/- or LXRbeta -/- mice, but not in LXRalpha -/-beta -/- mice. While SREBP-1 and ABCG1 are induced in liver, muscle and adipose tissue, the apoE, GLUT4 and LXRalpha genes are specifically induced only in adipose tissue. We suggest that an important aspect of LXRalpha auto-regulation in adipose tissue may be to increase the level of LXRalpha over a threshold level necessary for induced expression of certain target genes.


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