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Molecular and Cellular Biology, August 2003, p. 5780-5789, Vol. 23, No. 16
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.16.5780-5789.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Promoter-Specific Roles for Liver X Receptor/Corepressor Complexes in the Regulation of ABCA1 and SREBP1 Gene Expression

Brandee L. Wagner,1* Annabel F. Valledor,2 Gang Shao,1 Chris L. Daige,1 Eric D. Bischoff,1 Mary Petrowski,1 Kristen Jepsen,3 Sung Hee Baek,3 Richard A. Heyman,1 Michael G. Rosenfeld,3 Ira G. Schulman,1 and Christopher K. Glass2*

X-Ceptor Therapeutics, San Diego, California 92121,1 Division of Cellular and Molecular Medicine,2 Howard Hughes Medical Institute, University of California—San Diego, La Jolla, California 920933

Received 12 December 2002/ Returned for modification 3 February 2003/ Accepted 20 May 2003

Liver X receptors (LXRs) regulate the expression of genes involved in cholesterol and fatty acid homeostasis, including the genes for ATP-binding cassette transporter A1 (ABCA1) and sterol response element binding protein 1 (SREBP1). Loss of LXR leads to derepression of the ABCA1 gene in macrophages and the intestine, while the SREBP1c gene remains transcriptionally silent. Here we report that high-density-lipoprotein (HDL) cholesterol levels are increased in LXR-deficient mice, suggesting that derepression of ABCA1 and possibly other LXR target genes in selected tissues is sufficient to result in enhanced HDL biogenesis at the whole-body level. We provide several independent lines of evidence indicating that the repressive actions of LXRs are dependent on interactions with the nuclear receptor corepressor (NCoR) and the silencing mediator of retinoic acid and thyroid hormone receptors (SMRT). While dissociation of NCoR and SMRT results in derepression of the ABCA1 gene in macrophages, it is not sufficient for derepression of the SREBP1c gene. These findings reveal differential requirements for corepressors in the regulation of genes involved in cholesterol and fatty acid homeostasis and raise the possibility that these interactions may be exploited to develop synthetic ligands that selectively modulate LXR actions in vivo.

* Corresponding author. Mailing address for Brandee L. Wagner: X-Ceptor Therapeutics, Inc., 4757 Nexus Center Dr., Suite 200, San Diego, CA 92121. Phone: (858) 458-4541. Fax: (858) 458-4501. E-mail: bwagner{at}x-ceptor.com. Mailing address for Christopher K. Glass: Division of Cellular and Molecular Medicine, University of California—San Diego, La Jolla, CA 92039. Phone: (858) 534-6011. Fax: (858) 822-2127. E-mail: cglass{at}ucsd.edu.

Molecular and Cellular Biology, August 2003, p. 5780-5789, Vol. 23, No. 16
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.16.5780-5789.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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