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

凝血酶活化纤维蛋白溶解抑制剂（TAFI）通过去除细胞表面纤维蛋白或纤溶酶原受体蛋白上的c端赖氨酸残基而具有抗纤溶活性，在纤维蛋白溶解的调控中起重要作用。在本研究中，我们检测了肝细胞再生过程中TAFI的调控，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诱导的急性肝损伤可抑制血浆TAFI活性和肝脏TAFI mRNA水平，而该手术可显著提高肝纤溶酶活性和增殖细胞核抗原（PCNA）水平。在原代培养的大鼠肝细胞中，促生长培养条件下TAFI mRNA水平降低。用TAFI siRNA处理肝细胞可增加肝细胞上的纤溶酶数量，促进肝细胞增殖。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，TAFI基因表达下调，使肝细胞增殖发生。这是关于TAFI在细胞增殖所必需的细胞周围纤维蛋白溶解中的作用的第一篇报道。

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.