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Liver X Receptor 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, Research Triangle Park, North Carolina 27709,¹ Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina 27710,² Howard Hughes Medical Institute, Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, Texas 75390,³ Program in Molecular Medicine, University of Massachusetts Medical School, 373 Plantation Street, Worcester, Massachusetts 01605,⁴ China Medical University, Shenyang 110001, People's Republic of China⁵

Received 15 August 2007/ Returned for modification 26 September 2007/ Accepted 2 January 2008

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 peroxisome proliferator-activated receptor (PPAR) and PPAR coactivator 1 (PGC-1), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor (LXR) as a direct transcriptional inhibitor of β-adrenergic receptor-mediated, cyclic AMP-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/PGC-1 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.

Published ahead of print on 14 January 2008.

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