Liver X receptor alpha is a transcriptional repressor of the uncoupling protein 1 gene and the brown fat phenotype.

Wang H, Zhang Y, Yehuda-Shnaidman E, Medvedev AV, Kumar N, Daniel KW, Robidoux J, Czech MP, Mangelsdorf DJ, Collins S
Mol Cell Biol. 2008 28 (7): 2187-200

PMID: 18195045 · PMCID: PMC2268430 · DOI:10.1128/MCB.01479-07

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 gamma (PPARgamma) and PPARgamma coactivator 1alpha (PGC-1alpha), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor alpha (LXRalpha) as a direct transcriptional inhibitor of beta-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 LXRalpha binding site that overlaps with the PPARgamma/PGC-1alpha response element, resulting in the dismissal of PPARgamma. The ability of LXRalpha to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.

MeSH Terms (27)

Adaptor Proteins, Signal Transducing Adipocytes, Brown Adrenergic beta-Agonists Animals Body Temperature Cell Differentiation Cells, Cultured Colforsin DNA-Binding Proteins Enhancer Elements, Genetic Ion Channels Liver X Receptors Mice Mice, Inbred C57BL Mice, Knockout Mitochondria Mitochondrial Proteins Nuclear Proteins Nuclear Receptor Interacting Protein 1 Orphan Nuclear Receptors Oxygen Consumption PPAR gamma Receptors, Cytoplasmic and Nuclear RNA, Small Interfering Signal Transduction Transcription, Genetic Uncoupling Protein 1

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