Metabolic stress signaling mediated by mixed-lineage kinases
Metabolic stress signaling mediated by mixed-lineage kinases
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DOI：
10.1016/j.molcel.2007.07.008
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发表时间：
2007-08-03
期刊：
影响因子：
16
通讯作者：
Davis, Roger J.
中科院分区：
文献类型：
--
作者：
Jaeschke, Anja;Davis, Roger J.
饱和游离脂肪酸（FFA）是代谢应激的主要来源，其激活c-Jun NH 2-末端激酶（JINK）。FFA刺激的JNK通路与代谢综合征的标志相关，包括胰岛素抵抗。在这里，我们在小鼠中使用基因消融研究来证明混合谱系蛋白激酶（MLK）在该信号通路中的核心作用。饱和FFA导致MLK 3的蛋白激酶C（PKC）依赖性激活，随后通过需要MAP激酶激酶MKK 4和MKK 7的机制导致JNK活性增加。PKC、MLK 3、MKK 4或MKK 7表达的缺失阻止了FIFA刺激的JNK活化。总之，这些数据建立了介导代谢应激对胰岛素抵抗影响的信号通路。
Saturated free fatty acid (FFA) is a major source of metabolic stress that activates the c-Jun NH2-terminal kinase (JINK). This FFA-stimulated JNK pathway is relevant to hallmarks of metabolic syndrome, including insulin resistance. Here we used gene ablation studies in mice to demonstrate a central role for mixed-lineage protein kinases (MLK) in this signaling pathway. Saturated FFA causes protein kinase C (PKC)dependent activation of MLK3 that subsequently causes increased JNK activity by a mechanism that requires the MAP kinase kinases MKK4 and MKK7. Loss of PKC, MLK3, MKK4, or MKK7 expression prevents FIFA-stimulated JNK activation. Together, these data establish a signaling pathway that mediates effects of metabolic stress on insulin resistance.