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Mol. Cell. Biol. doi:10.1128/MCB.01479-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

LXR IS A TRANSCRIPTIONAL REPRESSOR OF THE UNCOUPLING PROTEIN-1 GENE AND THE BROWN FAT PHENOTYPE

The Endocrine Biology Program, The Hamner Institutes for Health Sciences, 6 Davis Drive, RTP, NC 27709; Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, 27710; Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390; Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, MA 01605; China Medical University, Shenyang, 110001, P.R.China

^* To whom correspondence should be addressed. Email: scollins{at}thehamner.org.

	Abstract

The adipocyte integrates crucial information about metabolic needs in order to balance energy intake, storage and expenditure. Whereas white adipose tissue stores energy, brown adipose tissue is a major site of energy dissipation through adaptive thermogenesis mediated by uncoupling protein-1 (UCP1) in mammals. In both white and brown adipose tissue, nuclear receptors and their coregulators such as PPAR and PGC1 play key roles in regulating their development and metabolic functions. Here we show the unexpected role of LXR as a direct transcriptional inhibitor of AR-mediated, cAMP-dependent Ucp1 gene expression through its binding to the critical enhancer region of the Ucp1 promoter. The mechanism of inhibition involves the differential recruitment of the corepressor RIP140 to an LXR binding site that overlaps with the PPAR/PGC1 response element resulting in the dismissal of PPAR. The ability of LXR to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.

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