Wang Haibo, Zhang Yuan, Yehuda-Shnaidman Einav, Medvedev Alexander V, Kumar Naresh, Daniel Kiefer W, Robidoux Jacques, Czech Michael P, Mangelsdorf David J, Collins Sheila
The Hamner Institutes for Health Sciences, 6 Davis Drive, P.O. Box 12137, Research Triangle Park, NC 27709, USA.
Mol Cell Biol. 2008 Apr;28(7):2187-200. doi: 10.1128/MCB.01479-07. Epub 2008 Jan 14.
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.
脂肪细胞整合有关代谢需求的关键信息，以平衡能量摄入、储存和消耗。白色脂肪组织储存能量，而棕色脂肪组织是哺乳动物中通过解偶联蛋白1（UCP1）介导的适应性产热进行能量消耗的主要部位。在白色和棕色脂肪组织中，核受体及其共调节因子，如过氧化物酶体增殖物激活受体γ（PPARγ）和PPARγ共激活因子1α（PGC-1α），在调节其发育和代谢功能中起关键作用。在这里，我们展示了肝脏X受体α（LXRα）的意外作用，它通过与Ucp1启动子的关键增强子区域结合，作为β-肾上腺素能受体介导的、环磷酸腺苷依赖性Ucp1基因表达的直接转录抑制剂。抑制机制涉及共抑制因子RIP140差异性募集到与PPARγ/PGC-1α反应元件重叠的LXRα结合位点，导致PPARγ被排除。LXRα以这种方式抑制能量消耗的能力为维持能量储存和利用之间的平衡提供了另一种机制。
