AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes
AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes
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DOI：
10.1074/jbc.273.24.14767
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发表时间：
1998-06-12
影响因子：
4.8
通讯作者：
Foufelle, F
中科院分区：
文献类型：
--
作者：
Foretz, M;Carling, D;Foufelle, F
虽然现在已经明确，参与葡萄糖和脂质代谢的许多基因在肝脏和脂肪组织中被高浓度的葡萄糖上调，但从葡萄糖到转录机制的信号传导途径仍然知之甚少。我们分析了葡萄糖对大鼠肝细胞脂肪酸合成酶基因表达的调控。葡萄糖（25 mM）诱导脂肪酸合成酶基因转录的激活，并且通过将细胞与蛋白磷酸酶1和2A的抑制剂冈田酸（okadaic acid）孵育，该作用显著降低。葡萄糖活化脂肪酸合酶基因表达的类似减少通过与5-氨基-咪唑甲酰胺核苷（AMP活化蛋白激酶的细胞渗透性活化剂）孵育获得。两者合计，这些结果表明，葡萄糖诱导的脂肪酸合成酶基因的表达涉及磷酸化/去磷酸化机制，并表明AMP激活的蛋白激酶在这一过程中起着重要作用。这是第一个表明AMP激活的蛋白激酶参与基因表达调控的证据。AMP激活的蛋白激酶是SNF 1的哺乳动物类似物，SNF 1是一种参与酵母中葡萄糖基因转录调节的激酶。
Although it is now clearly established that a number of genes involved in glucose and lipid metabolism are up-regulated by high glucose concentrations in both liver and adipose tissue, the signaling pathway arising from glucose to the transcriptional machinery is still poorly understood. We have analyzed the regulation of fatty acid synthase gene expression by glucose in cultured rat hepatocytes. Glucose (25 mM) induces an activation of the transcription of the fatty acid synthase gene, and this effect is markedly reduced by incubation of the cells with okadaic acid, an inhibitor of protein phosphatases 1 and 2A. A similar reduction in glucose-activated fatty acid synthase gene expression is obtained by incubation with 5-amino-imidazolecarboxamide riboside, a cell-permeable activator of the AMP-activated protein kinase. Taken together, these results indicate that the glucose-induced expression of the fatty acid synthase gene involves a phosphorylation/dephosphorylation mechanism and suggest that the AMP-activated protein kinase plays an important role in this process. This is the first evidence that implicates the AMP-activated protein kinase in the regulation of gene expression. AMP-activated protein kinase is the mammalian analog of SNF1, a kinase involved in yeast in the transcriptional regulation of genes by glucose.