Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice
Sustained activation of Rac1 in hepatic stellate cells promotes liver injury and fibrosis in mice
复制标题
DOI：
10.1002/hep.21375
复制
发表时间：
2006-11-01
期刊：
影响因子：
13.5
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Choi, Steve S.;Sicklick, Jason K.;Diehl, Anna Mae
Rac是Rho家族中的一种小的GTP结合蛋白，调节几种细胞功能，包括NADPH氧化酶的活化，NADPH氧化酶是活性氧（ROS）的主要细胞内产生者。从NADPH氧化酶遗传缺陷的小鼠中分离的肝星状细胞（HSC）产生较少的ROS，并且它们在慢性肝损伤期间的活化被消除，导致肝纤维化减少。因此，我们假设通过增加HSC中Rac的表达，HSC ROS的产生和活化将增强，纤维化恶化。为了实现这一点，我们使用了在α-平滑肌肌动蛋白（α-sma）启动子控制下表达组成型活性人Rac 1的转基因小鼠，因为α-sma表达在HSC活化过程中自发诱导。在原代Rac转基因HSC的培养过程中，转基因表达逐渐上调，这增加了HSC ROS的产生以及活化标志物和胶原蛋白的表达。同样地，用四氯化碳（CCl 4）处理的Rac小鼠比用CO 4处理的野生型小鼠积累了更多数量的活化HSC，并且有更多的肝损伤、肝细胞凋亡和肝纤维化以及更高的死亡率。总之，HSC中Rac的持续活化使其活化持续存在并加剧毒素诱导的肝损伤和纤维化，促使推测Rac可能是肝硬化患者的治疗靶点。
Rac, a small, GTP-binding protein in the Rho family, regulates several cellular functions, including the activation of NADPH oxidase, a major intracellular producer of reactive oxygen species (ROS). Hepatic stellate cells (HSCs) isolated from mice that are genetically deficient in NADPH oxidase produce less ROS, and their activation during chronic liver injury is abrogated, resulting in decreased liver fibrosis. Therefore, we hypothesized that HSC ROS production and activation would be enhanced, and fibrosis worsened, by increasing Rac expression in HSCs. To achieve this, we used transgenic mice that express constitutively active human Rac1 under the control of the a-smooth muscle actin (alpha-sma) promoter, because a-sma expression is induced spontaneously during HSC activation. Transgene expression was upregulated progressively during culture of primary Rac-transgenic HSCs, and this increased HSC ROS production as well as expression of activation markers and collagen. Similarly, Rac mice treated with carbon tetrachloride (CCl4) accumulated greater numbers of activated HSCs and had more liver damage, hepatocyte apoptosis, and liver fibrosis-as well as higher mortality-than CO4-treated wild-type mice. In conclusion, sustained activation of Rac in HSCs perpetuates their activation and exacerbates toxin-induced liver injury and fibrosis, prompting speculation that Rac may be a therapeutic target in patients with cirrhosis.