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Journal of Lipid Research, Vol. 45, 2052-2062, November 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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

Stine Marie Ulven^*, Knut Tomas Dalen^*, Jan-Åke Gustafsson and Hilde I. Nebb^1,*

^* Department of Nutrition, University of Oslo, N-0316 Oslo, Norway
Departments of Bioscience and Medical Nutrition, Novum, S-14186 Huddinge, Sweden

¹ To whom correspondence should be addressed. e-mail: h.i.nebb{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 LXR gene is highly induced in vivo and in vitro in mouse and human adipocytes in the presence of the synthetic LXR agonist T0901317. This autoregulation is caused by an identified LXR-responsive element motif in the mouse LXR promoter, which is conserved in the human LXR promoter. Using different LXR-deficient mice, we demonstrate that the basal expression level of LXR is increased in LXRß^–/– mice, whereas the basal expression level of LXRß is unchanged in LXR^–/– mice. The two LXRs 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-1 (SREBP-1), ATP binding cassette transporter A1 (ABCA1), ABCG1, as well as apolipoprotein E (apoE) are induced in vivo by T0901317 in wild-type, LXR^–/– or LXRß^–/– mice but not in LXR^–/–ß^–/– mice. Although SREBP-1 and ABCG1 are induced in liver, muscle, and adipose tissue, the apoE, glucose transporter-4 (GLUT4), and LXR genes are specifically induced only in adipose tissue.

We suggest that an important aspect of LXR autoregulation in adipose tissue may be to increase the level of LXR over a threshold level necessary to induce the expression of certain target genes.

Abbreviations: apoE, apolipoprotein E; CMC, carboxymethyl-cellulose; DR-4, direct repeat 4; GLUT4, glucose transporter-4; LXR, liver X receptor; LXRE, LXR-responsive element; PPAR, peroxisome proliferator-activated receptor ; RXR, retinoid X receptor; SREBP-1, sterol regulatory element binding protein-1; WAT, white adipose tissue

Supplementary key words liver X receptor • sterol regulatory element binding protein-1 • peroxisome proliferator-activated receptor • ATP binding cassette • lipid homeostasis • apolipoprotein E

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