The liver X receptor (LXR) and hepatic lipogenesis - The carbohydrate-response element-binding protein is a target gene of LXR
The liver X receptor (LXR) and hepatic lipogenesis - The carbohydrate-response element-binding protein is a target gene of LXR
复制标题
DOI：
10.1074/jbc.m605023200
复制
发表时间：
2007-01-05
影响因子：
4.8
通讯作者：
Repa, Joyce J.
中科院分区：
文献类型：
--
作者：
Cha, Ji-Young;Repa, Joyce J.
肝脏X受体，LXR α（NR 1H 3）和LXR β（NR 1H 2），是属于核激素受体超家族的配体激活的转录因子。LXR在胆固醇稳态和胆汁酸代谢中起关键作用。此外，对小鼠口服LXR激动剂导致肝脂肪酸合成和脂肪变性升高，富含甘油三酯的极低密度脂蛋白分泌增加，导致高甘油三酯血症。这种增加的肝脏脂肪生成在很大程度上归因于LXR依赖的固醇调节元件结合蛋白1c（SREBP-1c）表达的上调。然而，据报道，用合成的LXR激动剂T0901317治疗Srebp-1c缺失小鼠仍然导致许多脂肪生成基因的表达增强，这表明LXR可以增强肝脏脂肪生成的其他机制。在这份报告中，我们确定了碳水化合物反应元件结合蛋白（ChREBP）作为LXR的目标，独立地增强选择脂肪生成基因的上调。ChREBP启动子含有赋予受体依赖性结合和反式激活的功能性LXR结合位点。我们发现T0901317治疗小鼠与ChREBP靶基因肝型丙酮酸激酶的上调相关。因此，LXR的激活不仅通过增强的转录增加ChREBP mRNA，而且还调节ChREBP活性。这确立了LXR作为主脂肪生成转录因子，因为它直接调节SREBP-1c和ChREBP以增强肝脂肪酸合成。
The liver X receptors, LXR alpha (NR1H3) and LXR beta (NR1H2), are ligand-activated transcription factors that belong to the nuclear hormone receptor superfamily. LXRs play a critical role in cholesterol homeostasis and bile acid metabolism. In addition, oral administration of LXR agonists to mice results in elevated hepatic fatty acid synthesis and steatosis and increased secretion of triglyceride-rich very low density lipoprotein resulting in hypertriglyceridemia. This increased hepatic lipogenesis has been largely attributed to the LXR-dependent upregulation of sterol regulatory element-binding protein 1c (SREBP-1c) expression. However, it has been reported that treating Srebp-1c null mice with the synthetic LXR agonist T0901317 still results in enhanced expression of many lipogenic genes, suggesting additional mechanisms by which LXR can enhance hepatic lipogenesis. In this report, we identify the carbohydrate response element-binding protein (ChREBP) as an LXR target that independently enhances the up-regulation of select lipogenic genes. The ChREBP promoter contains functional LXR-binding sites that confer receptor-dependent binding and transactivation. We show that T0901317 treatment of mice is associated with up-regulation of the ChREBP target gene, liver-type pyruvate kinase. Therefore, activation of LXR not only increases ChREBP mRNA via enhanced transcription but also modulates ChREBP activity. This establishes LXR as a master lipogenic transcription factor, as it directly regulates both SREBP-1c and ChREBP to enhance hepatic fatty acid synthesis.