Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver
Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver
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DOI：
10.1073/pnas.0404297101
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发表时间：
2004-08-03
影响因子：
11.1
通讯作者：
Brown, MS
中科院分区：
文献类型：
--
作者：
Chen, GX;Liang, GS;Brown, MS
已知编码固醇调节元件结合蛋白1c（SREBP-1c）的基因的转录被肝脏中的胰岛素激活。所产生的SREBP-1c蛋白激活脂肪酸合成所需基因的转录。在这里，我们使用SREBP-1c启动子报告构建体来剖析新鲜分离的大鼠肝细胞中胰岛素激活的机制。数据显示，一个完整的胰岛素反应（增加6至11倍）需要两个肝X受体（LXR）的结合位点，这是由氧化固醇激活的核受体。这些结合位点的破坏不会降低基础转录，但会严重降低对胰岛素的反应。相反，SREBP和核因子Y紧密相连的结合位点的破坏大大降低了基础转录，但仍然允许对胰岛素的反应增加4至7倍。花生四烯酸，LXR激活的抑制剂，阻断了对胰岛素的反应。我们的结论是，胰岛素激活SREBP-1c启动子主要是通过增加LXRs的活性，可能是通过产生一种配体，激活LXRs或其异源二聚化伴侣，类维生素A X受体。核SREBPs和核因子Y起许可作用。
Transcription of the gene encoding sterol regulatory element-binding protein 1c (SREBP-1c) is known to be activated by insulin in the liver. The resultant SREBP-1c protein activates transcription of the genes required for fatty acid synthesis. Here, we use SREBP-1c promoter reporter constructs to dissect the mechanism of insulin activation in freshly isolated rat hepatocytes. The data show that a complete insulin response (increase of 6- to 11-fold) requires two binding sites for liver X receptors (LXRs), which are nuclear receptors that are activated by oxygenated sterols. Disruption of these binding sites did not lower basal transcription but severely reduced the response to insulin. In contrast, disruption of the closely linked binding sites for SREBPs and nuclear factor Y lowered basal transcription drastically but still permitted a 4- to 7-fold increase in response to insulin. Arachidonic acid, an inhibitor of LXR activation, blocked the response to insulin. We conclude that insulin activates the SREBP-1c promoter primarily by increasing the activity of LXRs, possibly through production of a ligand that activates LXRs or their heterodimerizing partner, the retinoid X receptor. Nuclear SREBPs and nuclear factor Y play permissive roles.