Shanghai University of Medicine & Health Sciences Affiliated Zhoupu Hospital, China.
Shanghai Jiaotong University Affiliated Sixth People's Hospital, China.
Ann Hepatol. 2021 Jan-Feb;20:100259. doi: 10.1016/j.aohep.2020.07.013. Epub 2020 Sep 24.
The activation of hepatic stellate cells (HSCs) is the main cause of liver fibrosis. The beneficial effects of fibroblast growth factor (FGF) 19 on liver fibrosis were recently reported. The S. miltiorrhiza as well as S. miltiorrhiza derived bioactive chemical components has shown prominent antifibrotic effects in liver fibrosis but the mechanism is still not fully understood. We aimed to investigate the bioactive compounds derived from S. miltiorrhiza which exerts antifibrotic effects in HSCs via regulating FGF19.
FGF19 level in culture media was determined by enzyme-linked immunosorbent assay. Cell proliferation was measured by Cell Counting Kit-8 assay. Further, mRNA and protein expressions were assessed by quantitative polymerase chain reaction and western blotting, respectively. Knocking down of FGF receptor 4 (FGFR4) by transfection with siRNA was used to confirm the role of FGF19/FGFR4 signaling.
Using the human HSC cell line LX-2, we screened several natural products and found that bioactive compounds isolated from Salvia miltiorrhiza, particularly salvianolic acid B, strongly upregulated FGF19 secretion by LX-2 cells. We further showed that salvianolic acid B inhibited lipopolysaccharide (LPS)-induced HSC proliferation and activation. LPS treatment may also reduce the mRNA and protein levels of FGF19 and its receptor FGFR4. Salvianolic acid B treatment restored the impaired expressions of FGF19 and FGFR4. Finally, FGFR4 knockdown abolished the antifibrotic effects of salvianolic acid B in the LPS-induced HSC activation model.
Salvianolic acid B prevented LPS-induced HSC proliferation and activation by enhancing antifibrotic FGF19/FGFR4 signaling.
肝星状细胞（HSCs）的激活是肝纤维化的主要原因。最近有报道称成纤维细胞生长因子（FGF）19 对肝纤维化有有益作用。丹参及其衍生的生物活性化学物质在肝纤维化中表现出明显的抗纤维化作用，但机制尚不完全清楚。我们旨在研究丹参衍生的生物活性化合物通过调节 FGF19 对 HSCs 发挥抗纤维化作用的机制。
通过酶联免疫吸附试验测定培养基中 FGF19 的水平。通过细胞计数试剂盒-8 测定细胞增殖。进一步通过定量聚合酶链反应和蛋白质印迹分别评估 mRNA 和蛋白质表达。通过转染 siRNA 敲低 FGF 受体 4（FGFR4）以确认 FGF19/FGFR4 信号的作用。
使用人 HSC 细胞系 LX-2，我们筛选了几种天然产物，发现丹参中的生物活性化合物，特别是丹酚酸 B，强烈地上调 LX-2 细胞的 FGF19 分泌。我们进一步表明，丹酚酸 B 抑制脂多糖（LPS）诱导的 HSC 增殖和激活。LPS 处理也可能降低 FGF19 及其受体 FGFR4 的 mRNA 和蛋白水平。丹酚酸 B 处理恢复了 LPS 诱导的 HSC 激活模型中受损的 FGF19 和 FGFR4 表达。最后，FGFR4 敲低消除了丹酚酸 B 在 LPS 诱导的 HSC 激活模型中的抗纤维化作用。
丹酚酸 B 通过增强抗纤维化的 FGF19/FGFR4 信号来防止 LPS 诱导的 HSC 增殖和激活。
