Department of Emergency Medicine, Nanfang Hospital, Southern Medical University, No. 1838, North of Guangzhou Avenue, Guangzhou City, Guangdong Province, 510515, China.
Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
Eur J Nutr. 2024 Dec;63(8):3255-3268. doi: 10.1007/s00394-024-03504-w. Epub 2024 Sep 26.
(-)-Epigallocatechin-3-O-gallate (EGCG), one of the green tea catechins, exhibits significant antioxidant properties that play an essential role in various diseases. However, the functional role and underlying mechanism of EGCG in stimulating of hepatic stellate cells (HSCs) remain unexplored in transcriptomics sequencing studies. The present study suggests that oral administration of EGCG at a dosage of 200 mg/kg/day for a duration of four weeks exhibits significant therapeutic potential in a murine model of liver fibrosis induced by CCl. The activation of HSCs in vitro was dose-dependently inhibited by EGCG. The sequencing analysis data reveled that EGCG exerted a regulatory effect on the calcium signal in mouse HSCs, resulting in a decrease in calcium ion concentration. Further analysis revealed that EGCG inhibited the expression of phospholipase C epsilon-1 (PLCE1) and inositol 1, 4, 5-trisphosphate (IP) in activated mouse HSCs. Additionally, EGCG contributes to the reduction the concentration of calcium ions by regulating PLCE1. After the knockdown of PLCE1, free calcium ion concentrations decreased, resulting in the inhibition of both cell proliferation and migration. Interestingly, the expression of PLCE1 and cytosolic calcium levels were regulated by reactive oxygen species(ROS). Furthermore, our findings suggest that ROS might inhibit the expression of PLCE1 by inhibiting TFEB, a transcription activator involved in the nuclear translocation process. Our study provided novel evidence regarding the regulatory effects of EGCG on activated HSCs (aHSCs) in mice by the calcium signaling pathway, emphasizing the crucial role of PLCE1 within the calcium signaling network of HSCs. The proposition was also made that PLCE1 holds promise as a novel therapeutic target for murine liver fibrosis.
（-）-表没食子儿茶素没食子酸酯（EGCG）是绿茶儿茶素之一，具有显著的抗氧化特性，在各种疾病中发挥着重要作用。然而，在转录组测序研究中，EGCG 刺激肝星状细胞（HSCs）的功能作用和潜在机制仍未得到探索。本研究表明，EGCG 以 200mg/kg/天的剂量口服给药，持续四周，在 CCl 诱导的肝纤维化小鼠模型中显示出显著的治疗潜力。EGCG 可剂量依赖性地抑制体外 HSCs 的活化。测序分析数据显示，EGCG 对小鼠 HSCs 中的钙信号发挥调节作用，导致钙离子浓度降低。进一步分析表明，EGCG 抑制激活的小鼠 HSCs 中磷脂酶 C ɛ-1（PLCE1）和肌醇 1,4,5-三磷酸（IP）的表达。此外，EGCG 通过调节 PLCE1 有助于降低钙离子浓度。PLCE1 敲低后，游离钙离子浓度降低，导致细胞增殖和迁移受到抑制。有趣的是，PLCE1 的表达和胞质钙离子水平受活性氧（ROS）调节。此外，我们的研究结果表明，ROS 通过抑制转录激活因子 TFEB 抑制 PLCE1 的表达，而 TFEB 参与核易位过程。我们的研究提供了关于 EGCG 通过钙信号通路调节小鼠激活的 HSCs（aHSCs）的新证据，强调了 PLCE1 在 HSCs 钙信号网络中的关键作用。还提出 PLCE1 可能成为治疗小鼠肝纤维化的新靶点。
