Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis
Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis
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DOI：
10.1073/pnas.0914798107
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发表时间：
2010-02-23
影响因子：
11.1
通讯作者：
Goldstein, Joseph L.
中科院分区：
文献类型：
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作者：
Li, Shijie;Brown, Michael S.;Goldstein, Joseph L.
胰岛素抵抗的糖尿病小鼠的肝脏表现出选择性胰岛素抵抗，表明胰岛素信号传导途径中的分叉：胰岛素失去其阻断葡萄糖产生的能力（即，它不能抑制PEPCK和其它脂肪生成基因），但它保留了刺激脂肪酸合成的能力（即，脂肪生成基因的持续增强）。增强的脂肪生成伴随着胰岛素刺激的编码SREBP-1c的mRNA的增加，SREBP-1c是一种激活整个脂肪生成程序的转录因子。在这里，我们报告了一个分支点的胰岛素信号通路，可能占选择性胰岛素抵抗。大鼠肝细胞暴露于胰岛素后，SREBP-1c mRNA增加25倍，PEPCK mRNA降低95%。胰岛素介导的两种mRNA的变化被PI 3 K和Akt抑制剂阻断，表明这两种途径都需要这些激酶。相比之下，亚纳摩尔浓度的雷帕霉素，mTORC 1激酶的抑制剂，阻断SREBP-1c的胰岛素诱导，但对PEPCK的胰岛素抑制没有影响。我们观察到雷帕霉素在大鼠和小鼠肝脏中具有相似的选择性作用，这些大鼠和小鼠在快速补饲方案下经历了胰岛素激增。mTORC 1的下游靶点S6激酶的特异性抑制剂不能阻断胰岛素对SREBP-1c的诱导作用，表明其下游途径与S6激酶不同。这些结果建立mTORC 1作为一个重要组成部分，在胰岛素调节途径的肝脏脂肪生成，但不是hepatogenesis，并可能有助于解决糖尿病啮齿类动物的肝脏中的选择性胰岛素抵抗的悖论。
The livers of insulin-resistant, diabetic mice manifest selective insulin resistance, suggesting a bifurcation in the insulin signaling pathway: Insulin loses its ability to block glucose production (i.e., it fails to suppress PEPCK and other genes of gluconeogenesis), yet it retains its ability to stimulate fatty acid synthesis (i.e., continued enhancement of genes of lipogenesis). Enhanced lipogenesis is accompanied by an insulin-stimulated increase in the mRNA encoding SREBP-1c, a transcription factor that activates the entire lipogenic program. Here, we report a branch point in the insulin signaling pathway that may account for selective insulin resistance. Exposure of rat hepatocytes to insulin produced a 25-fold increase in SREBP-1c mRNA and a 95% decrease in PEPCK mRNA. Insulin-mediated changes in both mRNAs were blocked by inhibitors of PI3K and Akt, indicating that these kinases are required for both pathways. In contrast, subnanomolar concentrations of rapamycin, an inhibitor of the mTORC1 kinase, blocked insulin induction of SREBP-1c, but had no effect on insulin suppression of PEPCK. We observed a similar selective effect of rapamycin in livers of rats and mice that experienced an insulin surge in response to a fastingre-feeding protocol. A specific inhibitor of S6 kinase, a downstream target of mTORC1, did not block insulin induction of SREBP-1c, suggesting a downstream pathway distinct from S6 kinase. These results establish mTORC1 as an essential component in the insulinregulated pathway for hepatic lipogenesis but not gluconeogenesis, and may help to resolve the paradox of selective insulin resistance in livers of diabetic rodents.