Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Surgical Operation, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Life Sci. 2021 Jul 1;276:119294. doi: 10.1016/j.lfs.2021.119294. Epub 2021 Mar 3.
Hepatic stellate cells (HSCs) are the major source of extracellular matrix (ECM)-producing myofibroblasts. When activated by multiple injuries, HSCs become proliferative, contractile, inflammatory and chemotactic and are characterized by enhanced ECM production, which plays a central role in hepatic fibrosis initiation and progression. In the present study, through bioinformatics analysis, we identified the abnormal upregulation of Peripheral Myelin Protein 22 (PMP22) in fibrotic murine liver. In CCl-induced hepatic fibrosis model in mice and TGF-β-activated hHSCs, PMP22 was observed remarkably upregulated. In TGF-β-stimulated hHSCs, PMP22 silencing hindered, whereas PMP22 overexpression aggravated TGF-β-induced hHSC activation. In CCl-induced hepatic fibrosis model in mice, PMP22 silencing improved CCl-caused liver damage and fibrotic changes. Through online tools prediction and experimental validation, miR-139-5p was found to bind to the 3'UTR of PMP22 and negatively regulate the expression of PMP22. In contrast to PMP22 silencing, miR-139-5p inhibition enhanced TGF-β-induced hHSC activation; the effects of miR-139-5p inhibition on TGF-β-induced hHSC activation were partially reversed by PMP22 silencing. In conclusion, we identify the abnormal upregulation of PMP22 in TGF-β-activated HSCs and CCl-induced hepatic fibrosis model in mice, as well as the pro-fibrotic role of PMP22 through aggravating TGF-β-induced HSCs activation. miR-139-5p targets the 3'UTR of PMP22 and inhibits PMP22 expression; miR-139-5p hinders TGF-β-induced HSCs activation through targeting PMP22.
肝星状细胞（HSCs）是产生细胞外基质（ECM）的肌成纤维细胞的主要来源。当受到多种损伤激活时，HSCs 会增殖、收缩、炎症和趋化，并表现出增强的 ECM 产生，这在肝纤维化的启动和进展中起着核心作用。在本研究中，通过生物信息学分析，我们发现纤维性小鼠肝脏中 Peripheral Myelin Protein 22（PMP22）异常上调。在 CCl 诱导的小鼠肝纤维化模型和 TGF-β 激活的 hHSCs 中，观察到 PMP22 显著上调。在 TGF-β 刺激的 hHSCs 中，PMP22 沉默抑制，而 PMP22 过表达加剧 TGF-β 诱导的 hHSC 激活。在 CCl 诱导的小鼠肝纤维化模型中，PMP22 沉默改善了 CCl 引起的肝损伤和纤维化变化。通过在线工具预测和实验验证，发现 miR-139-5p 结合到 PMP22 的 3'UTR 并负调控 PMP22 的表达。与 PMP22 沉默相反，miR-139-5p 抑制增强了 TGF-β 诱导的 hHSC 激活；miR-139-5p 抑制对 TGF-β 诱导的 hHSC 激活的影响部分被 PMP22 沉默逆转。总之，我们发现 TGF-β 激活的 HSCs 和 CCl 诱导的小鼠肝纤维化模型中 PMP22 异常上调，以及 PMP22 通过加剧 TGF-β 诱导的 HSCs 激活发挥促纤维化作用。miR-139-5p 靶向 PMP22 的 3'UTR 并抑制 PMP22 表达；miR-139-5p 通过靶向 PMP22 抑制 TGF-β 诱导的 HSCs 激活。
