Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes.
Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes.
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DOI：
10.1016/j.jhep.2011.03.019
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发表时间：
2012-01
影响因子：
25.7
通讯作者：
Jaeschke, Anja
中科院分区：
文献类型：
--
作者：
Sharma, Manju;Urano, Fumihiko;Jaeschke, Anja
饱和游离脂肪酸（SFA）刺激的c-Jun氨基末端激酶（JNK）激活与非酒精性脂肪性肝病（NAFLD）的发病机制相关。然而，负责SFA的影响的机制并不完全清楚。本研究的目的是确定SFA诱导肝细胞中JNK活化的分子机制。我们在Hepa 1c 1c 7和AML 12细胞系以及原代小鼠肝细胞中使用siRNA介导的敲除进行这些研究。目前SFA激活JNK的模型涉及内质网（ER）应激，其通过肌醇需要酶1（IRE 1 α）/凋亡调节激酶1（ASK 1）依赖性机制诱导JNK激活。在这里，我们发现SFA诱导的JNK激活在IRE 1 α和ASK 1不存在的情况下不受抑制。相反，我们表明，激活的小GTP结合蛋白Cdc 42和Rac 1是必需的SFA刺激MLK 3依赖性激活JNK在肝细胞中。此外，我们证明SFA诱导的肝细胞死亡不依赖于IRE 1 α，但依赖于Cdc 42，Rac 1和MLK 3。我们的研究结果表明，Cdc 42和Rac 1，而不是ER应激，是SFA刺激的信号通路的重要组成部分，调节MLK 3依赖性激活JNK在肝细胞中。
Saturated free fatty acid (SFA)-stimulated c-Jun NH2-terminal kinase (JNK) activation is associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the effects of SFA are incompletely understood. The goal of this study was to determine the molecular mechanisms by which SFA induce JNK activation in hepatocytes. We used siRNA-mediated knockdown in Hepa1c1c7 and AML12 cell lines, as well as primary mouse hepatocytes for these studies. The current model for JNK activation by SFA involves endoplasmic reticulum (ER) stress, which induces JNK activation through an inositol requiring enzyme 1 (IRE1α)/Apoptosis Regulating Kinase 1 (ASK1)–dependent mechanism. Here, we find that SFA-induced JNK activation is not inhibited in the absence of IRE1α and ASK1. Instead we show that activation of the small GTP-binding proteins Cdc42 and Rac1 is required for SFA-stimulated MLK3-dependent activation of JNK in hepatocytes. In addition, we demonstrate that SFA-induced cell death in hepatocytes is independent of IRE1α, but dependent on Cdc42, Rac1 and MLK3. Our results demonstrate that Cdc42 and Rac1, rather than ER stress, are important components of a SFA-stimulated signaling pathway that regulates MLK3-dependent activation of JNK in hepatocytes.
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影响因子：
25.7
作者：
Ibrahim SH;Akazawa Y;Cazanave SC;Bronk SF;Elmi NA;Werneburg NW;Billadeau DD;Gores GJ
通讯作者：
Gores GJ
影响因子：
3.7
作者：
Cellurale C;Weston CR;Reilly J;Garlick DS;Jerry DJ;Sluss HK;Davis RJ
通讯作者：
Davis RJ
影响因子：
4.8
作者：
Böck, BC;Vacratsis, PO;Gallo, KA
通讯作者：
Gallo, KA
影响因子：
16
作者：
Jaeschke, Anja;Davis, Roger J.
通讯作者：
Davis, Roger J.
影响因子：
3.9
作者：
Cnop, Miriam;Igoillo-Esteve, Mariana;Eizirik, Decio L.
通讯作者：
Eizirik, Decio L.