Liver X Receptor α Is a Transcriptional Repressor of the Uncoupling Protein 1 Gene and the Brown Fat Phenotype

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 peroxisome proliferator-activated receptor γ (PPARγ) and PPARγ coactivator 1α (PGC-1α), play key roles in regulating their development and metabolic functions. Here we show the unexpected role of liver X receptor α (LXRα) 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 LXRα binding site that overlaps with the PPARγ/PGC-1α response element, resulting in the dismissal of PPARγ. The ability of LXRα to dampen energy expenditure in this way provides another mechanism for maintaining a balance between energy storage and utilization.