Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells
Loss of Sept4 exacerbates liver fibrosis through the dysregulation of hepatic stellate cells
复制标题
DOI：
10.1016/j.jhep.2008.05.026
复制
发表时间：
2008-11-01
影响因子：
25.7
通讯作者：
Kinoshita, Makoto
中科院分区：
文献类型：
--
作者：
Iwaisako, Keiko;Hatano, Etsuro;Kinoshita, Makoto
背景/目标：胞膜蛋白是一种广泛存在的多功能支架蛋白，参与细胞骨架的组织、胞吐作用和其他细胞过程。我们揭示了静止的肝星状细胞（HSC）特异性表达的sept 4在肝脏中，并探讨sept 4系统在肝fibrosis.Methods的意义：我们分析了表达的α-平滑肌肌动蛋白（α-SMA），胶原蛋白和其他标志物在原代培养的HSC来自野生型和Sept 4（-/-）小鼠。我们比较了这些小鼠对四氯化碳治疗、胆管结扎或蛋氨酸/胆碱缺乏饮食诱导的肝纤维化的易感性。胶原沉积，肝纤维化的主要参数，定量组织化学（Masson的三色染色）和生化（羟脯氨酸含量）。结果：在体外，Sept 4 mRNA/蛋白显着下调HSC通过肌纤维母细胞转化。Sept 4（-/-）HSC显示正常形态和增殖，而与野生型HSC相比，通过α-SMA和胶原的上调监测的成肌纤维细胞转化加速。在体内，肝纤维化是一贯更严重的Sep 4（-/-）小鼠比野生型同窝出生的三个范例的肝炎/肝fibrosis.Conclusions：这些数据一致表明，HSC特异性sept 4亚基，也许septin系统参与抑制调制与肝脏疾病相关的肌纤维母细胞转化和纤维化。(C)2008年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background/Aims: Septins are ubiquitous and multifunctional scaffold proteins involved in cytoskeletal organization, exocytosis and other cellular processes. We disclose the quiescent hepatic stellate cells (HSCs)-specific expression of a septin subunit Sept4 in the liver, and explore the significance of the septin system in liver fibrosis.Methods: We analyzed the expression of alpha-smooth muscle actin (alpha-SMA), collagens and other markers in primary cultured HSCs derived from wild-type and Sept4(-/-) mice. We compared susceptibility of these mice to liver fibrosis induced by either carbon tetrachloride treatment, bile duct ligation or methionine/choline-deficient diet. Collagen deposition, the principal parameter of liver fibrosis, was quantified both histochemically (Masson's trichrome stain) and biochemically (hydroxyproline content).Results: In vitro, Sept4 mRNA/protein was remarkably downregulated in HSCs through myofibroblastic transformation. Sept4(-/-) HSCs showed normal morphology and proliferation, while myofibroblastic transformation as monitored by the upregulation of alpha-SMA and collagen was accelerated compared to wild-type HSCs. In vivo, liver fibrosis was consistently more severe in Sept4(-/-) mice than in wild-type littermates in all of the three paradigms of hepatitis/liver fibrosis.Conclusions: These data concordantly indicate that the HSC-specific septin subunit Sept4 and perhaps the septin system are involved in the suppressive modulation of myofibroblastic transformation and fibrogenesis associated with liver diseases. (C) 2008 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.