Liver fibrosis causes downregulation of miRNA-150 and miRNA-194 in hepatic stellate cells, and their overexpression causes decreased stellate cell activation
Liver fibrosis causes downregulation of miRNA-150 and miRNA-194 in hepatic stellate cells, and their overexpression causes decreased stellate cell activation
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DOI：
10.1152/ajpgi.00220.2009
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发表时间：
2010-01-01
影响因子：
4.5
通讯作者：
Zern, Mark A.
中科院分区：
文献类型：
--
作者：
Venugopal, Senthil K.;Jiang, Joy;Zern, Mark A.
Venugopal SK，姜军，金廷辉，李勇，王世生，Torok NJ，吴军，Zern MA。肝纤维化导致肝星状细胞miRNA-150和miRNA-194下调，其过表达导致星状细胞活化降低。[J] .中国生物医学工程学报，2016,31(2):559 - 561。首次发表于2009年11月5日；doi: 10.1152 / ajpgi.00220.2009。-肝星状细胞（HSC）的活化导致其增殖和细胞外基质（ECM）蛋白的分泌，从而导致肝纤维化。microRNAs （miRNAs）已被证明可以调节多种细胞功能，如增殖、分化和凋亡。因此，我们分析了假手术大鼠和胆管结扎大鼠分离的HSC中差异表达的mirna。与假手术动物相比，从纤维化大鼠分离的HSC中miRNA-150和miRNA-194两种mirna的表达减少。这两种mirna在LX-2细胞中过表达，并测定了它们抑制细胞增殖的能力，以及平滑肌α -肌动蛋白（SMA）（一种激活标志物）和I型胶原蛋白（一种ECM分泌标志物）的表达。与未处理细胞或非特异性表达mirna的细胞相比，这两种mirna的过表达导致增殖显著抑制（P < 0.05）， SMA和胶原I水平降低。接下来，利用生物信息学方法发现这两个mirna的蛋白靶点。C-myb被发现是miRNA-150的靶标，rac 1被发现是miRNA-194的靶标之一。因此，我们通过在LX-2细胞中过表达这两种mirna来研究这两种蛋白的表达，发现过表达miRNA-150和miRNA-194分别导致c-myb和rac 1表达的显著抑制。我们得出结论，miRNA-150和miRNA-194至少在一定程度上通过抑制c-myb和rac 1的表达来抑制HSC的激活和ECM的产生。
Venugopal SK, Jiang J, Kim T-H, Li Y, Wang S-S, Torok NJ, Wu J, Zern MA. Liver fibrosis causes downregulation of miRNA-150 and miRNA-194 in hepatic stellate cells, and their overexpression causes decreased stellate cell activation. Am J Physiol Gastrointest Liver Physiol 298: G101-G106, 2010. First published November 5, 2009; doi:10.1152/ajpgi.00220.2009.-Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis. microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation, and apoptosis. Hence, we have analyzed the miRNAs that were differentially expressed in HSC isolated from sham-operated and bile duct-ligated rats. Expression of two miRNAs, miRNA-150 and miRNA-194, was reduced in HSC isolated from fibrotic rats compared with sham-operated animals. These two miRNAs were overexpressed in LX-2 cells, and their ability to inhibit cell proliferation, the expression of smooth muscle alpha-actin (SMA), a marker for activation, and collagen type I, a marker for ECM secretion, was determined. Overexpression of these two miRNAs resulted in a significant inhibition of proliferation (P < 0.05) and reduced SMA and collagen I levels compared with either untreated cells or nonspecific miRNA-expressing cells. Next, the protein targets of these two miRNAs were found using bioinformatics approaches. C-myb was found to be a target for miRNA-150, and rac 1 was found to be one of the targets for miRNA-194. Therefore, we studied the expression of these two proteins by overexpressing these two miRNAs in LX-2 cells and found that overexpression of miRNA-150 and miRNA-194 resulted in a significant inhibition of c-myb and rac 1 expression, respectively. We conclude that both miRNA-150 and miRNA-194 inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac 1 expression.