Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu, Japan.
Department of Immunology, Mie University Graduate School of Medicine, Tsu, Japan.
Am J Pathol. 2018 May;188(5):1195-1203. doi: 10.1016/j.ajpath.2018.01.007. Epub 2018 Feb 16.
Protein S is a vitamin K-dependent glycoprotein produced mainly in the liver with anticoagulant, anti-inflammatory, immune-modulatory, and antiapoptotic properties. Protein S exacerbates acute liver injury by prolonging the survival of liver immune cells. However, the effect of protein S on chronic liver injury and fibrosis is unknown. Here, we investigated whether human protein S can affect chronic liver injury and fibrosis. Liver injury/fibrosis was induced by carbon tetrachloride injection in mice overexpressing human protein S and in wild-type mice. Human protein S transgenic mice receiving carbon tetrachloride showed significantly higher circulating levels of liver transaminases, increased liver expression of inflammatory cytokines, significantly more extended liver fibrosis, and areas with DNA breakage after chronic injury compared with wild-type mice. Wild-type mice infused with exogenous human protein S exhibited exacerbated liver injury and increased number of hepatic stellate cells compared with untreated mice. Human protein S inhibited apoptosis and increased Akt pathway activation in hepatic stellate cells. The antiapoptotic activity of protein S may play a role in chronic liver injury and subsequent liver fibrosis.
蛋白质 S 是一种维生素 K 依赖性糖蛋白，主要在肝脏中产生，具有抗凝、抗炎、免疫调节和抗凋亡作用。蛋白质 S 通过延长肝免疫细胞的存活时间来加重急性肝损伤。然而，蛋白质 S 对慢性肝损伤和纤维化的影响尚不清楚。在这里，我们研究了人蛋白质 S 是否会影响慢性肝损伤和纤维化。通过在过表达人蛋白质 S 的小鼠和野生型小鼠中注射四氯化碳来诱导肝损伤/纤维化。与野生型小鼠相比，接受四氯化碳处理的人蛋白质 S 转基因小鼠的循环肝转氨酶水平明显升高，肝脏炎症细胞因子的表达增加，肝纤维化明显延长，慢性损伤后的 DNA 断裂区域增加。与未处理的小鼠相比，输注外源性人蛋白质 S 的野生型小鼠的肝损伤加重，肝星状细胞数量增加。蛋白质 S 抑制肝星状细胞的凋亡并增加 Akt 通路的激活。蛋白质 S 的抗凋亡活性可能在慢性肝损伤和随后的肝纤维化中起作用。
