MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling.
MicroRNA-125b Promotes Hepatic Stellate Cell Activation and Liver Fibrosis by Activating RhoA Signaling.
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MicroRNA-125b 通过激活 RhoA 信号传导促进肝星状细胞激活和肝纤维化。
DOI：
10.1016/j.omtn.2018.04.016
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发表时间：
2018-09-07
期刊：
影响因子：
--
通讯作者：
Zhuang SM
中科院分区：
文献类型：
--
作者：
You K;Li SY;Gong J;Fang JH;Zhang C;Zhang M;Yuan Y;Yang J;Zhuang SM
miR-125 b在不同疾病中经常失调。肝星状细胞（hepatic stellate cells，HSC）的活化是肝纤维化发生过程中的一个重要环节。然而，miR-125 b在HSC活化和肝纤维化中的作用及其机制尚不清楚。在此，我们发现miR-125 b在体内肝纤维化过程中和体外培养激活后在HSC中上调，但在肝细胞中不上调。抑制miR-125 b可抑制培养活化的原代HSC中促纤维化基因的表达，并降低基础和转化生长因子β（TGF-β）诱导的α-平滑肌肌动蛋白（α-SMA）表达和永生化HSC细胞系的细胞收缩。相反，miR-125 b的异位表达促进α-SMA表达和HSC收缩。此外，体内拮抗miR-125 b显著减轻了CCl 4处理小鼠的肝纤维化。从机制上讲，在HSC中过表达miR-125 b通过直接靶向含有StAR相关脂质转移（START）结构域13（Stard 13）（一种RhoA特异性GTP酶激活蛋白）来增强RhoA活性，而敲低miR-125 b则废除RhoA激活。抑制RhoA或其下游分子Mrtf-A和Srf可减弱miR-125 b诱导的α-SMA表达和HSC收缩。因此，我们的研究结果确定了HSC中的miR-125 b-Stard 13-RhoA-α-SMA信号级联反应，并强调了其在肝纤维化中的重要性。
miR-125b is frequently dysregulated in different diseases. Activation of hepatic stellate cells (HSCs) is a critical event during liver fibrogenesis. However, the function and its underlying mechanism of miR-125b in HSC activation and liver fibrosis are still unknown. Here, we showed that miR-125b was upregulated in HSCs, but not in hepatocytes, during hepatic fibrogenesis in vivo and upon culture activation in vitro. Inhibition of miR-125b suppressed the expression of profibrogenic genes in culture-activated primary HSCs and reduced the basal and transforming growth factor β (TGF-β)-induced alpha-smooth muscle actin (α-SMA) expression and cell contraction of the immortalized HSC cell line. In contrast, ectopic expression of miR-125b promoted α-SMA expression and HSC contraction. Moreover, antagonizing miR-125b in vivo significantly alleviated liver fibrosis in CCl4-treated mice. Mechanistically, overexpression of miR-125b in HSCs enhanced RhoA activity by directly targeting StAR-related lipid transfer (START) domain containing 13 (Stard13), a RhoA-specific GTPase-activating protein, whereas knockdown of miR-125b abrogated RhoA activation. Furthermore, inhibition of RhoA or its downstream molecules, Mrtf-A and Srf, attenuated the miR-125b-induced α-SMA expression and HSC contraction. Therefore, our findings identify a miR-125b-Stard13-RhoA-α-SMA signaling cascade in HSCs and highlight its importance in hepatic fibrosis.
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