Glycyrrhetinic Acid-Induced MiR-663a Alleviates Hepatic Stellate Cell Activation by Attenuating the TGF-β/Smad Signaling Pathway
Glycyrrhetinic Acid-Induced MiR-663a Alleviates Hepatic Stellate Cell Activation by Attenuating the TGF-β/Smad Signaling Pathway
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甘草次酸诱导的 MiR-663a 通过减弱 TGF-β/Smad 信号通路减轻肝星状细胞活化
DOI：
10.1155/2020/3156267
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发表时间：
2020-05-12
影响因子：
--
通讯作者：
Zhang, Hui
中科院分区：
文献类型：
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作者：
Guo, Xin-Xin;Yang, Wen-Na;Zhang, Hui
甘草次酸（GA）是甘草提取物中甘草酸的水解产物，已被用于治疗肝纤维化疾病。然而，GA抗纤维化作用的分子机制仍不清楚。miR-663 a的参与及其在TGF-β-1诱导的肝星状细胞（HSC）活化中的作用尚不清楚。本研究旨在探讨miR-663 a在HSC活化中的作用及GA的抗肝纤维化机制。miR-663 a在TGF-β处理的HSC中表达下调。miR-663 a过表达抑制HSC增殖。TGF-β 1是miR-663 a的直接靶基因。miR-663 a减轻HSC活化，伴随着α-平滑肌肌动蛋白（α-SMA）、人α 2（I）胶原蛋白（COL 1A 2）、TGF-β 1、TGF-β RI、Smad 4、p-Smad 2和p-Smad 3表达的降低。GA上调HSC中miR-663 a的表达并抑制TGF-β/Smad通路。进一步的研究表明，miR-663 a抑制剂处理逆转了GA介导的TGF-β 1、TGF-β RI、Smad 4、p-Smad 2、p-Smad 3、α-SMA和CoL 1A 2在TGF-β 1处理的HSC中的下调。这些结果表明，miR-663 a抑制HSC增殖和活化以及TGF-β/Smad信号通路，突出表明miR-663 a可用作肝纤维化的治疗靶点。GA通过靶向miR-663 a/TGF-β/Smad信号通路至少部分抑制HSC增殖和活化。
Glycyrrhetinic acid (GA), a hydrolysate of glycyrrhizic acid from licorice root extract, has been used to treat liver fibrotic diseases. However, the molecular mechanism involved in the antifibrotic effects of GA remains unclear. The involvement of miR-663a and its roles in TGF-beta-1-induced hepatic stellate cell (HSC) activation remains unclear. In this study, we investigated the roles of miR-663a in the activation of HSCs and the antifibrosis mechanism of GA. MiR-663a expression was downregulated in TGF-beta-treated HSCs. The overexpression of miR-663a inhibited HSC proliferation. TGF-beta-1was confirmed as a direct target gene of miR-663a. MiR-663a alleviated HSC activation, concomitant with decreased expression of alpha-smooth muscle actin (alpha-SMA), human alpha 2 (I) collagen (COL1A2), TGF-beta 1, TGF-beta RI, Smad4, p-Smad2, and p-Smad3. GA upregulated miR-663a expression and inhibited the TGF-beta/Smad pathway in HSCs. Further studies showed that miR-663a inhibitor treatment reversed GA-mediated downregulation of TGF-beta 1, TGF-beta RI, Smad4, p-Smad2, p-Smad3, alpha-SMA, and CoL1A2 in TGF-beta 1-treated HSCs. These results show that miR-663a suppresses HSC proliferation and activation and the TGF-beta/Smad signaling pathway, highlighting that miR-663a can be utilized as a therapeutic target for hepatic fibrosis. GA inhibits, at least in part, HSC proliferation and activation via targeting the miR-663a/TGF-beta/Smad signaling pathway.