Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis.
Focal Adhesion Kinase Regulates Hepatic Stellate Cell Activation and Liver Fibrosis.
复制标题
局灶粘附激酶调节肝星状细胞活化和肝纤维化
DOI：
10.1038/s41598-017-04317-0
复制
发表时间：
2017-06-22
影响因子：
4.6
通讯作者：
Ding Q
中科院分区：
文献类型：
--
作者：
Zhao XK;Yu L;Cheng ML;Che P;Lu YY;Zhang Q;Mu M;Li H;Zhu LL;Zhu JJ;Hu M;Li P;Liang YD;Luo XH;Cheng YJ;Xu ZX;Ding Q
了解肝纤维化的潜在分子机制对于开发有效的治疗方法非常重要。本研究表明，病灶黏附激酶（FAK）在体外促进肝星状细胞（hsc）活化和体内肝纤维化进展中起关键作用。FAK活化与纤维化活组织中α-平滑肌肌动蛋白（α-SMA）和胶原蛋白表达增加有关。转化生长因子β -1 （TGF-β1）诱导FAK激活具有时间和剂量依赖性。FAK激活先于α-SMA在造血干细胞中的表达。抑制FAK活化可阻断TGF-β1处理的hsc中α-SMA和胶原的表达，抑制应激纤维的形成。此外，抑制FAK活化可显著降低TGF-β1处理的HSC迁移和小GTPase活化，诱导凋亡信号。重要的是，FAK抑制剂在体内可减弱肝纤维化蛋白，并显著降低肝纤维化动物模型中胶原和α-SMA的表达。这些数据表明FAK在HSC激活和肝纤维化进展中起着重要作用，FAK信号通路可能是肝纤维化的潜在靶点。
Understanding the underlying molecular mechanisms of liver fibrosis is important to develop effective therapy. Herein, we show that focal-adhesion-kinse (FAK) plays a key role in promoting hepatic stellate cells (HSCs) activationin vitroand liver fibrosis progressionin vivo. FAK activation is associated with increased expression of α-smooth muscle actin (α-SMA) and collagen in fibrotic live tissues. Transforming growth factor beta-1 (TGF-β1) induces FAK activation in a time and dose dependent manner. FAK activation precedes the α-SMA expression in HSCs. Inhibition of FAK activation blocks the α-SMA and collagen expression, and inhibits the formation of stress fibers in TGF-β1 treated HSCs. Furthermore, inhibition of FAK activation significantly reduces HSC migration and small GTPase activation, and induces apoptotic signaling in TGF-β1 treated HSCs. Importantly, FAK inhibitor attenuates liver fibrosisin vivoand significantly reduces collagen and α-SMA expression in an animal model of liver fibrosis. These data demonstrate that FAK plays an essential role in HSC activation and liver fibrosis progression, and FAK signaling pathway could be a potential target for liver fibrosis.