The nuclear receptor LXR is a glucose sensor
The nuclear receptor LXR is a glucose sensor
复制标题
DOI：
10.1038/nature05449
复制
发表时间：
2007-01-11
期刊：
影响因子：
64.8
通讯作者：
Saez, Enrique
中科院分区：
文献类型：
--
作者：
Mitro, Nico;Mak, Puiying A.;Saez, Enrique
肝脏在葡萄糖稳态中起着核心作用，因为它具有产生和消耗葡萄糖的独特能力（1）。进食时，葡萄糖流入触发肝细胞中的基因表达变化，以抑制内源性葡萄糖产生，并将过量葡萄糖转化为糖原或脂肪酸储存在脂肪组织中（2）。这一过程由胰岛素控制，尽管关于胰岛素是否直接或间接作用于肝脏存在争议（3）。除了刺激胰腺胰岛素释放外，葡萄糖还调节ChREBP的活性，ChREBP是一种调节脂肪生成的转录因子（4）。在这里，我们描述了另一种机制，葡萄糖决定自己的命运：我们表明，葡萄糖结合并刺激肝脏X受体（LXR），一个核受体，协调肝脏脂质代谢的转录活性。D-葡萄糖和D-葡萄糖-6-磷酸是LXR-α和LXR-β的直接激动剂。葡萄糖在肝脏中预期的生理浓度下激活LXR，并诱导LXR靶基因的表达，其功效与氧化固醇（已知的LXR配体）相似。需要LXR表达的胆固醇稳态基因在用葡萄糖饮食重新喂养的禁食小鼠的肝脏和肠中上调，表明葡萄糖是内源性LXR配体。我们的研究结果确定LXR作为一个转录开关，整合肝脏葡萄糖代谢和脂肪酸合成。
The liver has a central role in glucose homeostasis, as it has the distinctive ability to produce and consume glucose(1). On feeding, glucose influx triggers gene expression changes in hepatocytes to suppress endogenous glucose production and convert excess glucose into glycogen or fatty acids to be stored in adipose tissue(2). This process is controlled by insulin, although debate exists as to whether insulin acts directly or indirectly on the liver(3). In addition to stimulating pancreatic insulin release, glucose also regulates the activity of ChREBP, a transcription factor that modulates lipogenesis(4). Here we describe another mechanism whereby glucose determines its own fate: we show that glucose binds and stimulates the transcriptional activity of the liver X receptor (LXR), a nuclear receptor that coordinates hepatic lipid metabolism. D-Glucose and D-glucose-6-phosphate are direct agonists of both LXR-alpha and LXR-beta. Glucose activates LXR at physiological concentrations expected in the liver and induces expression of LXR target genes with efficacy similar to that of oxysterols, the known LXR ligands. Cholesterol homeostasis genes that require LXR for expression are upregulated in liver and intestine of fasted mice re-fed with a glucose diet, indicating that glucose is an endogenous LXR ligand. Our results identify LXR as a transcriptional switch that integrates hepatic glucose metabolism and fatty acid synthesis.