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Originally published In Press as doi:10.1194/jlr.M300312-JLR200 on January 1, 2004

Papers In Press, published online ahead of print April 1, 2004
J. Lipid Res., doi:10.1194/jlr.M300312-JLR200
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Journal of Lipid Research, Vol. 45, 616-625, April 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Liver X receptors are regulators of adipocyte gene expression but not differentiation

: identification of apoD as a direct target

Sarah Hummasti*,{dagger}, Bryan A. Laffitte§,{dagger}{dagger}, Michael A. Watson{dagger}{dagger}, Cristin Galardi{dagger}{dagger}, Lily C. Chao**, Lakshman Ramamurthy§§, John T. Moore{dagger}{dagger} and Peter Tontonoz1,2,*,{dagger},§

* Molecular Biology Institute, University of California, Los Angeles, CA 90095
{dagger} Howard Hughes Medical Institute, University of California, Los Angeles, CA 90095
§ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA 90095
** Department of Pediatrics, University of California, Los Angeles, CA 90095
{dagger}{dagger} High Thoughput Biology, GlaxoSmithKline, Research Triangle Park, NC 27709
§§ Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709

2 To whom correspondence should be addressed. e-mail: ptontonoz{at}mednet.ucla.edu

The liver X receptors {alpha} and ß (LXR{alpha} and LXRß) have been shown to play important roles in lipid homeostasis in liver and macrophages, however, their function in adipose tissue is not well defined. Both LXRs are highly expressed in fat, and the expression of LXR{alpha} increases during adipogenesis. Furthermore, LXR{alpha} expression is induced by peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}), the master regulator of fat cell differentiation. Here we investigate the role of LXRs in adipocyte differentiation and gene expression and their potential crosstalk with the PPAR{gamma} pathway. We demonstrate that LXR agonists have no significant effect on the differentiation of 3T3-F442A or 3T3-L1 preadipocytes in vitro and do not alter the expression of differentiation-linked PPAR{gamma} target genes in vivo. Moreover, retroviral expression of LXR{alpha} in NIH-3T3 cells does not alter the adipogenic potential of these cells and neither augments nor inhibits the action of PPAR{gamma}. However, transcriptional profiling studies reveal that LXRs are important regulators of adipocyte gene expression. We identify the multifunction lipid carrier protein apolipoprotein D and the lipogenic protein Spot 14 as LXR responsive genes both in vitro and in vivo.

Thus, although LXRs do not influence adipocyte differentiation per se, these receptors are likely to play an important role in the modulation of lipid metabolism in adipocytes.

Abbreviations: apoD, apolipoprotein D; FACoA, FA coenzyme A; GARG-16, glucocorticoid attenuated response gene 16; GLUT4, glucose transporter-4; OSBP, oxysterol-binding protein; LXR, liver X receptor; LXRE, LXR response element; PGAR, PPAR{gamma} angioprotein related; PPAR{gamma}, peroxisome proliferator-activated receptor {gamma}; RAR{gamma}, retinoic acid receptor {gamma}; RXR{alpha}, retinoid X receptor {alpha}; SC5D, sterol-C5-desaturase; SREBP-1c, sterol-regulatory element binding protein 1c

Supplementary key words adipocyte • apolipoprotein • differentiation • liver X receptor • nuclear receptor • peroxisome proliferator-activated receptor


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