Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways
Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways
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DOI：
10.1002/jcp.22833
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发表时间：
2012-03-01
影响因子：
5.6
通讯作者：
Kojima, Soichi
中科院分区：
文献类型：
--
作者：
Kuo, Ting-Fang;Tatsukawa, Hideki;Kojima, Soichi
非酒精性脂肪性肝炎（NASH）是一种进行性脂肪肝，与酒精性脂肪性肝炎（ASH）在组织学上有相似之处，包括脂肪积累、肝细胞凋亡和肝脏纤维组织，但导致肝细胞凋亡的分子机制尚不清楚。我们之前报道过，在乙醇处理的肝细胞核中诱导的转谷氨酰胺酶2 (TG2)，交联并使转录因子Sp1失活，导致肝细胞凋亡。在这项研究中，我们研究了类似的变化是否涉及NASH，如果是，TG2和交联Sp1 （CLSp1）是如何被诱导的。在NASH患者中，核TG2和CLSp1的形成升高，凋亡诱导因子（AIF）的激活增加，细胞色素c的释放增加。在用游离脂肪酸（FFAs）处理的Hc人正常肝细胞中，生化分析显示乙醇和FFAs会引起脂肪积累、内质网（ER）应激、核因子κ B （NFB）和核TG2的增加。Salubrinal是内质网应激诱导的胰腺内质网激酶（PERK）信号通路的选择性抑制剂，可抑制NF？B活化，核TG2表达，凋亡，只有在FFAs诱导下，而不是乙醇诱导。这些结果提示FFAs可增加内质网应激，导致核NF？通过perk依赖途径激活B和诱导TG2，导致TG2介导的凋亡伴随Sp1的交联和失活、AIF的激活和细胞色素的释放。物理学报，27(2):1133 - 1134,2012。(C) 2011 Wiley期刊公司
Non-alcoholic steatohepatitis (NASH), a progressive form of fatty liver, shares histological similarities with alcoholic steatohepatitis (ASH), including accumulated fat, hepatic apoptosis, and fibrous tissues in the liver, but the molecular mechanisms responsible for hepatic apoptosis remain unclear. We previously reported that transglutaminase 2 (TG2), induced in the nuclei of ethanol-treated hepatocytes, crosslinks and inactivates the transcription factor Sp1, leading to hepatic apoptosis. In this study, we investigated whether a similar change is involved in NASH, and if so, how TG2 and crosslinked Sp1 (CLSp1) are induced. Elevated nuclear TG2 and CLSp1 formation was demonstrated in NASH patients, as well as increased activation of apoptosis inducing factor (AIF) and release of cytochrome c. In Hc human normal hepatocytes treated with free fatty acids (FFAs), biochemical analyses revealed that ethanol and FFAs provoked fat accumulation, endoplasmic reticulum (ER) stress, increased nuclear factor kappa B (NFB), and nuclear TG2. Salubrinal, a selective inhibitor of the ER stress-induced pancreatic ER kinase (PERK) signaling pathway, inhibited NF?B activation, nuclear TG2 expression, and apoptosis only if it was induced by FFAs, but not by ethanol. These results suggest that FFAs could increase ER stress and lead to nuclear NF?B activation and TG2 induction through PERK-dependent pathways, resulting in TG2-mediated apoptosis accompanying crosslinking and inactivation of Sp1, activation of AIF, and release of cytochrome c. J. Cell. Physiol. 227: 11301137, 2012. (C) 2011 Wiley Periodicals, Inc.