The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
The Key Laboratory of Major Autoimmune Diseases, Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; The Key Laboratory of Anti-inflammatory of Immune Medicines, Ministry of Education, Hefei, China; Institute for Liver Diseases of Anhui Medical University, Hefei, China.
Mol Immunol. 2019 Mar;107:29-40. doi: 10.1016/j.molimm.2019.01.004. Epub 2019 Jan 11.
Yes-associated protein (YAP) is a significant downstream protein in the Hippo signaling pathway with important functions in cell proliferation, apoptosis, invasion and migration. YAP also plays a role in the progression and development of various liver diseases. In hepatic fibrosis development and reversion, the proliferation and apoptosis of activated hepatic stellate cells (HSCs) play a critical role. However, the contribution of YAP to hepatic fibrosis progression and reversion and the underlying mechanism have not been investigated. Here we investigated the expression and function of YAP in the proliferation and apoptosis of activated HSCs. We found that YAP expression was increased in liver fibrosis tissues from CCl-induced model mice and restored to normal level after stopping CCl injection and 6 weeks of spontaneously recovery. YAP expression was elevated in HSC-T6 cells treated with TGF-β1 and recovered after MDI treatment. Silencing of YAP inhibited the activation and proliferation of HSC-T6 cells stimulated by TGF-β1. In addition, the apoptosis of activated HSC-T6 cells silenced for YAP was slightly enhanced. Furthermore, over-expression of YAP repressed the reversion of activated HSC-T6 cells mediated by MDI reversal. We found that HSC-T6 cells activated by TGF-β1 showed higher levels of nuclear YAP compared with MDI-treated cells, indicating that YAP was activated in HSC-T6 cells treated by TGF-β1. We also found that loss of YAP attenuated Wnt/β-catenin pathway activity in activated HSC-T6 cells. Treatment of VP, an inhibitor of the YAP-TEAD complex, reduced both activation and proliferation of HSC-T6 cells and increased apoptosis. Together these results indicated that reduced expression of YAP contributes to acquisition of the quiescent phenotype in HSCs. Our results suggest that YAP may be a useful target in HSCs activation and reversion.
Yes 相关蛋白（YAP）是 Hippo 信号通路的重要下游蛋白，在细胞增殖、凋亡、侵袭和迁移中具有重要功能。YAP 还在各种肝脏疾病的进展和发展中发挥作用。在肝纤维化的发展和逆转中，活化的肝星状细胞（HSCs）的增殖和凋亡起着关键作用。然而，YAP 对肝纤维化进展和逆转的贡献及其潜在机制尚未得到研究。在这里，我们研究了 YAP 在活化的 HSCs 增殖和凋亡中的表达和功能。我们发现 CCl 诱导模型小鼠肝纤维化组织中 YAP 表达增加，停止 CCl 注射并自发恢复 6 周后恢复正常水平。TGF-β1 处理的 HSC-T6 细胞中 YAP 表达升高，MDI 处理后恢复。沉默 YAP 抑制 TGF-β1 刺激的 HSC-T6 细胞的激活和增殖。此外，沉默 YAP 的活化 HSC-T6 细胞的凋亡略有增强。此外，过表达 YAP 抑制 MDI 逆转介导的活化 HSC-T6 细胞的逆转。我们发现，与 MDI 处理的细胞相比，TGF-β1 激活的 HSC-T6 细胞中核 YAP 水平较高，表明 YAP 在 TGF-β1 处理的 HSC-T6 细胞中被激活。我们还发现，YAP 的缺失减弱了 TGF-β1 激活的 HSC-T6 细胞中 Wnt/β-catenin 通路的活性。YAP-TEAD 复合物抑制剂 VP 的处理降低了 HSC-T6 细胞的激活和增殖，并增加了细胞凋亡。这些结果表明，YAP 的表达降低有助于 HSCs 获得静止表型。我们的研究结果表明，YAP 可能是 HSCs 激活和逆转的一个有用靶点。
