p38 mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis
p38 mitogen-activated protein kinase plays a stimulatory role in hepatic gluconeogenesis
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DOI：
10.1074/jbc.m506223200
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发表时间：
2005-12-30
影响因子：
4.8
通讯作者：
Collins, S
中科院分区：
文献类型：
--
作者：
Cao, WH;Collins, QF;Collins, S
肝脏新生对于维持空腹血糖水平至关重要，并且是糖尿病患者餐后和空腹高血糖的主要原因。葡萄糖异生是由胰高血糖素启动的经典cAMP/蛋白激酶A依赖性过程，其在禁食期间和糖尿病中在血液中升高。在这项研究中，我们已经表明，p38丝裂原活化蛋白激酶（p38）被激活，在肝脏禁食和原代肝细胞胰高血糖素或毛喉素。在小鼠中，用化学抑制剂或小干扰RNA阻断p38后，空腹血糖水平降低。在研究其机制时，抑制p38抑制了肝脏中的新生血管形成，沿着关键新生血管形成基因的表达，包括磷酸烯醇丙酮酸羧激酶和葡萄糖-6-磷酸酶。过氧化物酶体增殖物激活受体γ辅激活因子1 α和环磷酸腺苷反应元件结合蛋白已被证明是肝脏糖异生的重要介质。我们已经证明，抑制p38阻止了PPAR γ共激活因子1 α基因的转录以及cAMP反应元件结合蛋白的磷酸化。总之，我们在体外和体内研究的结果定义了一个模型，其中cAMP依赖性激活的基因参与的p38通路依赖于p38，从而增加了一个新的球员，我们不断发展的理解这种生理学。
Hepatic gluconeogenesis is essential for maintaining blood glucose levels during fasting and is the major contributor to postprandial and fasting hyperglycemia in diabetes. Gluconeogenesis is a classic cAMP/protein kinase A-dependent process initiated by glucagon, which is elevated in the blood during fasting and in diabetes. In this study, we have shown that p38 mitogen-activated protein kinase (p38) was activated in liver by fasting and in primary hepatocytes by glucagon or forskolin. Fasting plasma glucose levels were reduced upon blockade of p38 with either a chemical inhibitor or small interference RNA in mice. In examining the mechanism, inhibition of p38 suppressed gluconeogenesis in liver, along with expression of key gluconeogenic genes, including phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha and cAMP-response element-binding protein have been shown to be important mediators of hepatic gluconeogenesis. We have shown that inhibition of p38 prevented transcription of the PPAR gamma coactivator 1 alpha gene as well as phosphorylation of cAMP-response element-binding protein. Together, our results from in vitro and in vivo studies define a model in which cAMP-dependent activation of genes involved in gluconeogenesis is dependent upon the p38 pathway, thus adding a new player to our evolving understanding of this physiology.