Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes
Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes
复制标题
DOI：
10.1073/pnas.96.22.12737
复制
发表时间：
1999-10-26
影响因子：
11.1
通讯作者：
Foufelle, F
中科院分区：
文献类型：
--
作者：
Foretz, M;Guichard, C;Foufelle, F
肝脏葡萄糖激酶在葡萄糖代谢中起关键作用，如与葡萄糖激酶突变相关的异常和组织特异性敲除的后果所强调的。在肝脏中，葡萄糖激酶转录绝对依赖于胰岛素的存在。目前尚不清楚介导胰岛素效应的顺式元件和反式作用因子;大多数胰岛素应答基因也是如此。我们先前已经表明，转录因子固醇调节元件结合蛋白-lc的肝表达，（SREBP-1c）是由胰岛素激活的，我们在这里显示，在肝细胞的原代培养物中，腺病毒介导的SREBP-1c显性负性形式的转导抑制了胰岛素对内源性葡萄糖激酶表达的作用，相反，在没有胰岛素的情况下，腺病毒介导的显性阳性形式的SREBP-1c的转导克服了葡萄糖激酶表达的胰岛素依赖性。肝脂肪酸合成酶和Spot-14是胰岛素/葡萄糖依赖性基因。对于后一类基因，SREBP-1c的显性阳性形式消除了胰岛素存在的必要性，而葡萄糖增强了SREBP-1c对其表达的影响。此外，培养的肝细胞中脂质积累的胰岛素依赖性被SREBP-1c的显性阳性形式克服。我们认为SREBP-1c是胰岛素作用于肝脏基因表达的主要介质，也是肝脏葡萄糖/脂质代谢的关键调节因子。
Hepatic glucokinase plays a key role in glucose metabolism as underlined by the anomalies associated with glucokinase mutations and the consequences of tissue-specific knock-out, In the liver, glucokinase transcription is absolutely dependent on the presence of insulin. The cis-elements and trans-acting factors that mediate the insulin effect are presently unknown; this is also the case for most insulin-responsive genes. We have shown previously that the hepatic expression of the transcription factor sterol regulatory element binding protein-lc (SREBP-1c) is activated by insulin, We show here in primary cultures of hepatocytes that the adenovirus-mediated transduction of a dominant negative form of SREBP-1c inhibits the insulin effect on endogenous glucokinase expression, Conversely, in the absence of insulin, the adenovirus-mediated transduction of a dominant positive form of SREBP-1c overcomes the insulin dependency of glucokinase expression. Hepatic fatty acid synthase and Spot-14 are insulin/glucose-dependent genes. For this latter class of genes, the dominant positive form of SREBP-1c obviates the necessity for the presence of insulin, whereas glucose potentiates the effect of SREBP-1c on their expression, In addition, the insulin dependency of lipid accumulation in cultured hepatocytes is overcome by the dominant positive form of SREBP-1c. We propose that SREBP-1c is a major mediator of insulin action on hepatic gene expression and a key regulator of hepatic glucose/lipid metabolism.