Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China.
Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, 230032, China; Postdoctoral Station of Clinical Medicine of Anhui Medical University, Hefei, Anhui, China.
Eur J Pharmacol. 2021 Nov 15;911:174462. doi: 10.1016/j.ejphar.2021.174462. Epub 2021 Sep 15.
Liver fibrosis is a persistent pathological repair of chronic liver injury, which is characterized by excessive deposition of collagen-dominated extracellular matrix (ECM). It is well known that hepatic fibrosis can be reversed in the absence of etiology. Studies have shown that long non-coding RNA (Lnc RNA) maternally expressed gene3 (MEG3) has strong effects on the activation of hepatic stellata cells (HSCs). However, the function of MEG3 in the reversal of liver fibrosis has not been studied. In this experiment, we studied the content expression, function, and part of the potential mechanism of MEG3 in reversing liver fibrosis. In in vivo and in vitro models, we found that MEG3 was down-regulated during the formation of liver fibrosis, while it was up-regulated during the reversal of liver fibrosis. Then, it was found that the silencing of MEG3 could gradually restore the activity of the inactivated LX-2 cells, Overexpression of MEG3 can inhibit the activation of LX-2 cells, accelerate the reversal of liver fibrosis. Through catRAPID analysis, it was found that NLR family CARD domain containing 5 (NLRC5) may be a target of MEG3. We found that, after MEG3 silencing, NLRC5 expression was upregulated in LX-2 cells in the reverse phase, while, after MEG3 overexpression, NLRC5 expression was decreased. Further, we verified that MEG3 can target NLRC5 through RNA pull down experiment. Therefore, MEG3 may inhibit the activation of hepatic stellate cells by targeting NLRC5, thus accelerating the reversal of hepatic fibrosis.
肝纤维化是慢性肝损伤的持续病理性修复，其特征是胶原为主的细胞外基质（ECM）过度沉积。众所周知，在没有病因的情况下，肝纤维化可以逆转。研究表明，长链非编码 RNA（LncRNA）母系表达基因 3（MEG3）对肝星状细胞（HSCs）的激活具有很强的作用。然而，MEG3 在肝纤维化逆转中的作用尚未得到研究。在本实验中，我们研究了 MEG3 在肝纤维化逆转中的含量表达、功能及部分潜在机制。在体内和体外模型中，我们发现 MEG3 在肝纤维化形成过程中下调，而在肝纤维化逆转过程中上调。然后发现，沉默 MEG3 可以逐渐恢复失活的 LX-2 细胞的活性，过表达 MEG3 可以抑制 LX-2 细胞的激活，加速肝纤维化的逆转。通过 catRAPID 分析，发现 NOD 样受体家族 C ARD 结构域包含 5（NLRC5）可能是 MEG3 的一个靶标。我们发现，沉默 MEG3 后，LX-2 细胞在逆转相 NLRC5 的表达上调，而过表达 MEG3 后，NLRC5 的表达降低。进一步通过 RNA 下拉实验验证了 MEG3 可以靶向 NLRC5。因此，MEG3 可能通过靶向 NLRC5 抑制肝星状细胞的激活，从而加速肝纤维化的逆转。
