School of Life Sciences and Health Engineering, Jiangnan University, Wuxi, Jiangsu, China.
Jiangsu Center Pharmacodynamic Research and Evaluation, China Pharmaceutical University, Nanjing, China.
Clin Mol Hepatol. 2023 Apr;29(2):465-481. doi: 10.3350/cmh.2022.0327. Epub 2023 Feb 20.
BACKGROUND/AIMS: Disrupted bile acid regulation and accumulation in the liver can contribute to progressive liver damage and fibrosis. However, the effects of bile acids on the activation of hepatic stellate cells (HSCs) remain unclear. This study investigated the effects of bile acids on HSC activation during liver fibrosis, and examined the underlying mechanisms.
The immortalized HSCs, LX-2 and JS-1cells were used for the in vitro study. in vitro, the adeno-associated viruses adeno-associated virus-sh-S1PR2 and JTE-013 were used to pharmacologically inhibit the activity of S1PR2 in a murine model of fibrosis induced by a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet. Histological and biochemical analyses were performed to study the involvement of S1PR2 in the regulation of fibrogenic factors as well as the activation properties of HSCs.
S1PR2 was the predominant S1PR expressed in HSCs and was upregulated during taurocholic acid (TCA) stimulation and in cholestatic liver fibrosis mice. TCA-induced HSC proliferation, migration and contraction and extracellular matrix protein secretion were inhibited by JTE-013 and a specific shRNA targeting S1PR2 in LX-2 and JS-1 cells. Meanwhile, treatment with JTE-013 or S1PR2 deficiency significantly attenuated liver histopathological injury, collagen accumulation, and the expression of fibrogenesis-associated genes in mice fed a DDC diet. Furthermore, TCAmediated activation of HSCs through S1PR2 was closely related to the yes-associated protein (YAP) signaling pathway via p38 mitogen-activated protein kinase (p38 MAPK).
TCA-induced activation of the S1PR2/p38 MAPK/YAP signaling pathways plays a vital role in regulating HSC activation, which might be therapeutically relevant for targeting cholestatic liver fibrosis.
背景/目的：胆汁酸在肝脏中的调节和积累紊乱可导致进行性肝损伤和纤维化。然而，胆汁酸对肝星状细胞（HSCs）激活的影响尚不清楚。本研究旨在探讨胆汁酸在肝纤维化过程中对 HSC 激活的影响，并研究其潜在机制。
本研究使用永生化的 HSCs（LX-2 和 JS-1 细胞）进行体外研究。在体外，使用腺相关病毒 adeno-associated virus-sh-S1PR2 和 JTE-013 抑制纤维化诱导的 3,5-二乙氧羰基-1,4-二氢胶原（DDC）饮食模型中小鼠 S1PR2 的活性。进行组织学和生化分析以研究 S1PR2 在调节纤维生成因子以及 HSCs 激活特性中的作用。
S1PR2 是 HSCs 中表达最丰富的 S1PR，在牛磺胆酸（TCA）刺激和胆汁淤积性肝纤维化小鼠中上调。TCA 诱导的 HSC 增殖、迁移和收缩以及细胞外基质蛋白分泌在 LX-2 和 JS-1 细胞中被 JTE-013 和靶向 S1PR2 的特异性 shRNA 抑制。同时，用 JTE-013 或 S1PR2 缺乏治疗显著减轻了 DDC 饮食喂养的小鼠的肝组织病理损伤、胶原积累和纤维化相关基因的表达。此外，TCA 通过 S1PR2 介导的 HSCs 激活与 p38 丝裂原活化蛋白激酶（p38 MAPK）相关的 yes 相关蛋白（YAP）信号通路密切相关。
TCA 诱导的 S1PR2/p38 MAPK/YAP 信号通路的激活在调节 HSC 激活中起关键作用，这可能与靶向胆汁淤积性肝纤维化的治疗有关。
