A novel function of thrombin activatable fibrinolysis inhibitor during rat liver regeneration and in growth-promoted hepatocytes in primary culture

凝血酶激活的纤溶抑制剂在大鼠肝再生和原代培养中促进生长的肝细胞中的新功能

• 批准号: 17580084
• 负责人: SEKT Taiichiro
• 金额: $ 2.37万
• 依托单位: Nihon University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17580084/
• 关键词: hepatocyte; liver; TAFI; fibrinolvsis; plasminogen; siRNA; TAF1; regeneration

Thrombin-activatable fibrinolysis inhibitor (TAFI) exhibits anti-fibrinolytic activity by removing C-terminal lysine residues from fibrin or plasminogen receptor proteins on the cellular surface, and plays an important role in the regulation of fibrinolysis. In this study, we examined the regulation of TAFI in hepatocytes during liver regeneration, and revealed its pivotal role in hepatocyte proliferation. In rat models, partial hepatectomy or CC1_4-induced acute liver injury suppressed the levels of plasma TAFI activity and hepatic TAFI mRNA, whereas this operation markedly increased both the hepatic plasmin activity and the level of proliferating cell nuclear antigen (PCNA). In primary cultures of rat hepatocytes, the TAFI mRNA level was decreased under growth-promoting culture conditions. Treatment of the hepatocytes with TAFI siRNA increased the amount of plasmin on the hepatocytes and promoted hepatocyte proliferation. We concluded that TAFI regulates plasmin activity through its enzymatic activity whereby it reduces the plasminogen-binding capacity of the hepatocytes. The TAFI gene expression is down-regulated for hepatocyte proliferation to occur by producing a fibrinolytic microenvironment suitable for cell growth. This is the first report on the role of TAFI in the pericellular fibrinolysis necessary for cellular proliferation.

凝血酶激活的纤溶抑制剂（TAFI）通过去除细胞表面的纤维蛋白或纤溶酶原受体蛋白的C末端赖氨酸残基而表现出抗纤溶活性，在纤溶调节中发挥重要作用。在本研究中，我们研究了肝再生过程中肝细胞中TAFI的调节，并揭示了其在肝细胞增殖中的关键作用。在大鼠模型中，部分肝切除或CC1_4诱导的急性肝损伤抑制了血浆TAFI活性和肝脏TAFI mRNA的水平，而该手术显着增加了肝脏纤溶酶活性和增殖细胞核抗原（PCNA）的水平。在大鼠肝细胞的原代培养物中，TAFI mRNA 水平在促生长培养条件下降低。用TAFI siRNA处理肝细胞增加了肝细胞上纤溶酶的量并促进了肝细胞增殖。我们得出结论，TAFI 通过其酶活性调节纤溶酶活性，从而降低肝细胞的纤溶酶原结合能力。通过产生适合细胞生长的纤溶微环境，下调 TAFI 基因表达，从而促进肝细胞增殖。这是关于 TAFI 在细胞增殖所需的细胞周纤维蛋白溶解中的作用的第一份报告。

项目成果

A role of surface-bound plasminogen in the liver regeneration in rat

表面结合型纤溶酶原在大鼠肝再生中的作用

• 发表时间: 2007
• 作者: N.;Okumura;Y.;Maeda;S.;Shimonishi;T.;Seki;T.;Ariga
• 通讯作者: Ariga

Annexin A3-Expressing Cellular Phenotypes Emerge from Necrotic Lesion in the Pericentral Area in 2-Acetylaminofluoren/Carbon Tetrachloride-Treated Rat Livers

2-乙酰氨基芴/四氯化碳处理的大鼠肝脏中央区域坏死病灶出现膜联蛋白 A3 表达细胞表型

• 发表时间: 2007
• 期刊: Bioscience, biotechnology and biochemistry
• 作者: Yoshimasa Ito;Takenori Watanabe;Shunsuke Nagatomo;T. Seki;S. Niimi;T. Ariga
• 通讯作者: T. Ariga

Connexin 32 down-regulates the fibronolytic factors in metastatic renal cell carcinoma cells.

连接蛋白 32 下调转移性肾细胞癌细胞中的纤溶因子。

• 发表时间: 2006
• 期刊: Life Science (in press)
• 作者: Harashirna;M.;Niimi;S.;Koyanagi;H.;Hyuga;M.;Noma;S.;Seki;T.;Ariga;T.;Kawanishi;T.;Hayakawa;T;M.Harashima;H.Hagiwara
• 通讯作者: H.Hagiwara

A role of surface-bound plasminogen in the liver regeneration in rat.

表面结合纤溶酶原在大鼠肝脏再生中的作用。

• 发表时间: 2007
• 作者: N.;Okumura;Y.;Maeda;S.;Shimonishi;T.;Seki;T.;Ariga;Okumura N
• 通讯作者: Okumura N

Cell Surface-Bound Plasminogen Regulates Hepatocyte Proliferation Through a uPA-Dependent Mechanism

• DOI: 10.1271/bbb.70126
• 发表时间: 2007-06
• 期刊: Bioscience, Biotechnology, and Biochemistry
• 作者: Nobuaki Okumura;T. Seki;T. Ariga