Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis.
Glycogen synthase kinase-3 (GSK-3) inhibition attenuates hepatocyte lipoapoptosis.
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DOI：
10.1016/j.jhep.2010.09.039
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发表时间：
2011-04
影响因子：
25.7
通讯作者：
Gores GJ
中科院分区：
文献类型：
--
作者：
Ibrahim SH;Akazawa Y;Cazanave SC;Bronk SF;Elmi NA;Werneburg NW;Billadeau DD;Gores GJ
饱和游离脂肪酸诱导肝细胞脂肪凋亡，这是非酒精性脂肪性肝炎的一个关键病理特征。饱和游离脂肪酸棕榈酸酯通过内质网应激途径诱导肝细胞脂肪凋亡，导致 c-Jun-N 末端 (JNK) 激活。糖原合成酶激酶 (GSK)-3 是一种丝氨酸/苏氨酸激酶，也可能促进 JNK 激活。因此，我们的目的是确定 GSK-3 抑制是否会抑制棕榈酸诱导的 JNK 激活和脂肪细胞凋亡。我们使用小鼠原代肝细胞、Huh-7 和 Hep3B 细胞系进行这些研究。棕榈酸酯诱导的 GSK-3 激活通过其底物糖原合酶的磷酸化来鉴定。 GSK-3 抑制剂 IX 和 enzastaurin 的 GSK-3 药理抑制显着减少 PA 介导的脂肪凋亡。更重要的是，Huh-7 细胞中的 GSK-3α 或 GSK-3β 亚型被 shRNA 稳定且选择性地敲低，显示出对棕榈酸酯诱导的细胞毒性的抵抗力。 GSK-3 药理学抑制剂和 GSK-3α 或 GSK-3β 的 shRNA 靶向敲低也抑制了棕榈酸酯对 JNK 的激活。 JNK 激活在一定程度上通过诱导促凋亡效应子 p53 上调的凋亡调节剂 (PUMA) 的表达来促进脂肪凋亡。与这一概念一致，GSK-3 药理学抑制也降低了暴露于棕榈酸酯期间的 PUMA 细胞蛋白水平。另一方面，GSK-3 抑制剂并不能阻止 PA 诱导 ER 应激。总之，我们的结果表明 GSK-3 激活促进 JNK 依赖性细胞毒性信号级联反应，最终导致脂肪凋亡。
Saturated free fatty acids induce hepatocyte lipoapoptosis, a key pathologic feature of nonalcoholic steatohepatitis. The saturated free fatty acid palmitate induces hepatocyte lipoapoptosis via an endoplasmic reticulum stress pathway resulting in c-Jun-N-terminal (JNK) activation. Glycogen synthase kinase (GSK)-3 is a serine/threonine kinase which may also promote JNK activation. Thus our aim was to determine if GSK-3 inhibition suppresses palmitate induced JNK activation and lipoapoptosis. We employed mouse primary hepatocytes, Huh-7 and Hep3B cell lines for these studies. Palmitate-induced GSK-3 activation was identified by phosphorylation of its substrate glycogen synthase. GSK-3 pharmacologic inhibition, by GSK-3 inhibitor IX and enzastaurin, significantly reduced PA-mediated lipoapoptosis. More importantly, Huh-7 cells in which either GSK-3α or GSK-3β isoforms were stably and selectively knocked down by shRNA displayed resistance to palmitate-induced cytotoxicity. GSK-3 pharmacological inhibitors and shRNA-targeted knockdown of GSK-3α or GSK-3β also suppressed JNK activation by palmitate. JNK activation, in part, promotes lipoapotosis by inducing expression of the pro-apoptotic effector p53-upregulated modulator of apoptosis (PUMA). Consistent with this concept, GSK-3 pharmacologic inhibition also reduced PUMA cellular protein levels during exposure to palmitate. On the other hand, the GSK-3 inhibitors did not prevent PA induction of ER stress. In CONCLUSION, our results suggest GSK-3 activation promotes a JNK-dependent cytotoxic signaling cascade culminating in lipoapoptosis.
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细胞角蛋白-18片段水平为非酒精性脂肪性肝炎的无创生物标志物：一项多中心验证研究。
影响因子：
13.5
作者：
Feldstein, Ariel E.;Wieckowska, Anna;Lopez, A. Rocio;Liu, Yao-Chang;Zein, Nizar N.;McCullough, Arthur J.
通讯作者：
McCullough, Arthur J.
影响因子：
25.7
作者：
Akazawa Y;Cazanave S;Mott JL;Elmi N;Bronk SF;Kohno S;Charlton MR;Gores GJ
通讯作者：
Gores GJ
影响因子：
13.5
作者：
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通讯作者：
Hobbs, HH
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4
作者：
Kim, AJ;Shi, YY;Werstuck, GH
通讯作者：
Werstuck, GH
影响因子：
13.5
作者：
Langer, Daniel A.;Das, Amitava;Shah, Vijay H.
通讯作者：
Shah, Vijay H.