Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism
Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism
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DOI：
10.1016/j.bbrc.2005.12.029
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发表时间：
2006-02-10
影响因子：
3.1
通讯作者：
Towle, HC
中科院分区：
文献类型：
--
作者：
Tsatsos, NG;Towle, HC
碳水化合物反应元件结合蛋白（ChREBP）是一种转录因子，介导肝细胞基因表达的葡萄糖反应性变化。在目前的葡萄糖调节模型中，低葡萄糖下ChREBP的抑制反应于cAMP依赖性蛋白激酶（PKA）介导的残基S196、S626的磷酸化。和/或T666。在葡萄糖增加的条件下，ChREBP的激活仅仅是由于这些抑制性磷酸化的逆转。为了测试这个模型，我们分析了缺乏一个或多个PKA位点的ChREBP突变形式，发现这些形式的ChREBP仍然需要葡萄糖激活。此外，在低葡萄糖条件下，培养的肝细胞中的cAMP水平可忽略不计，表明PKA不应具有活性。最后，总的ChREBP磷酸化没有改变响应改变葡萄糖水平。我们的结论是，除了其抑制PKA，葡萄糖激活的ChREBP涉及的第二种机制，是独立的PKA磷酸化。(c)2005年爱思唯尔公司All rights reserved.
Carbohydrate response element binding protein (ChREBP) is a transcription factor that mediates glucose-responsive changes in gene expression in hepatocytes. In the current model for glucose regulation, inhibition of ChREBP in low glucose occurs in response to cAMP-dependent protein kinase (PKA)-mediated phosphorylation of residues S196, S626. and/or T666. Activation of ChREBP in conditions of increased glucose results simply from reversal of these inhibitory phosphorylations. To test this model, we analyzed mutant forms of ChREBP that lack one or more of the proposed PKA sites and found that these forms of ChREBP still require glucose for activation. Additionally, cAMP levels in cultured hepatocytes were negligible in low glucose conditions, indicating PKA should not be active. Finally, overall ChREBP phosphorylation did not change in response to altered glucose levels. We conclude that in addition to its repression by PKA, glucose activation of ChREBP involves a second mechanism that is independent of PKA phosphorylation. (c) 2005 Elsevier Inc. All rights reserved.