E3 ubiquitin ligase synoviolin is involved in liver fibrogenesis.
E3 ubiquitin ligase synoviolin is involved in liver fibrogenesis.
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DOI：
10.1371/journal.pone.0013590
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发表时间：
2010-10-25
期刊：
影响因子：
3.7
通讯作者：
Nakajima T
中科院分区：
文献类型：
--
作者：
Hasegawa D;Fujii R;Yagishita N;Matsumoto N;Aratani S;Izumi T;Azakami K;Nakazawa M;Fujita H;Sato T;Araya N;Koike J;Tadokoro M;Suzuki N;Nagata K;Senoo H;Friedman SL;Nishioka K;Yamano Y;Itoh F;Nakajima T
慢性肝损伤导致肝纤维化，其特征在于富含胶原的细胞外基质的积累。然而，E3泛素连接酶参与肝纤维化胶原合成的机制尚不完全清楚。本研究旨在探讨E3泛素连接酶滑膜蛋白（Syno）在肝纤维化中的作用。在CCl 4诱导的肝损伤模型和人肝硬化组织中分析滑膜素在肝脏中的表达和定位。在慢性肝损伤模型中，比较了野生型（wt）和Syno+/−小鼠之间的肝纤维化程度和活化肝星状细胞（HSC）数量。我们比较了野生型和Syno+/−小鼠之间活化HSC的凋亡率。我们还分析了滑膜素对胶原蛋白合成的影响，在细胞系从HSC（LX-2）使用siRNA-滑膜素和突变体滑膜素，其中E3连接酶活性被废除。此外，我们使用定量RT-PCR、蛋白质印迹和胶原测定比较了野生型和Syno−/−小鼠胚胎成纤维细胞（MEF）之间的胶原合成;然后，我们用化学方法分析了Syno−/− MEF细胞中胶原的定位。在肝损伤模型以及肝硬化中，滑膜小提琴在活化的HSC中上调，而Syno+/−小鼠的肝纤维化明显少于野生型小鼠。在Syno+/−小鼠中，活化的HSC数量减少，其中一些细胞显示凋亡。此外，胶原蛋白在LX-2细胞中的表达上调滑膜蛋白过表达，而滑膜蛋白敲低导致胶原蛋白表达减少。此外，在Syno−/− MEF细胞中，细胞内和分泌的成熟胶原的量显著减少，并且前胶原异常地积聚在内质网中。我们的研究结果表明E3泛素连接酶滑膜蛋白在肝纤维化中的重要性。
Chronic hepatic damage leads to liver fibrosis, which is characterized by the accumulation of collagen-rich extracellular matrix. However, the mechanism by which E3 ubiquitin ligase is involved in collagen synthesis in liver fibrosis is incompletely understood. This study aimed to explore the involvement of the E3 ubiquitin ligase synoviolin (Syno) in liver fibrosis. The expression and localization of synoviolin in the liver were analyzed in CCl4-induced hepatic injury models and human cirrhosis tissues. The degree of liver fibrosis and the number of activated hepatic stellate cells (HSCs) was compared between wild type (wt) and Syno+/− mice in the chronic hepatic injury model. We compared the ratio of apoptosis in activated HSCs between wt and Syno+/− mice. We also analyzed the effect of synoviolin on collagen synthesis in the cell line from HSCs (LX-2) using siRNA-synoviolin and a mutant synoviolin in which E3 ligase activity was abolished. Furthermore, we compared collagen synthesis between wt and Syno−/− mice embryonic fibroblasts (MEF) using quantitative RT-PCR, western blotting, and collagen assay; then, we immunohistochemically analyzed the localization of collagen in Syno−/− MEF cells. In the hepatic injury model as well as in cirrhosis, synoviolin was upregulated in the activated HSCs, while Syno+/− mice developed significantly less liver fibrosis than in wt mice. The number of activated HSCs was decreased in Syno+/− mice, and some of these cells showed apoptosis. Furthermore, collagen expression in LX-2 cells was upregulated by synoviolin overexpression, while synoviolin knockdown led to reduced collagen expression. Moreover, in Syno−/− MEF cells, the amounts of intracellular and secreted mature collagen were significantly decreased, and procollagen was abnormally accumulated in the endoplasmic reticulum. Our findings demonstrate the importance of the E3 ubiquitin ligase synoviolin in liver fibrosis.
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DOI：
10.1073/pnas.95.16.9500
发表时间：
1998-08-04
影响因子：
11.1
作者：
Ratziu, V;Lalazar, A;Friedman, SL
通讯作者：
Friedman, SL
DOI：
10.1073/pnas.82.24.8681
发表时间：
1985-12-01
影响因子：
11.1
作者：
FRIEDMAN, SL;ROLL, FJ;BISSELL, DM
通讯作者：
BISSELL, DM
影响因子：
10.5
作者：
Amano, T;Yamasaki, S;Nakajima, T
通讯作者：
Nakajima, T
影响因子：
3.5
作者：
Kaneko, M;Ishiguro, M;Nomura, Y
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Nomura, Y
影响因子：
4.8
作者：
Mehtani, S;Gong, QM;Frankfater, A
通讯作者：
Frankfater, A