Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-β signaling pathway
Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-β signaling pathway
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DOI：
10.1096/fj.202201954r
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发表时间：
2023-05-01
期刊：
影响因子：
4.8
通讯作者：
Zhang, Lin
中科院分区：
文献类型：
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作者：
Liao, Yang;Zhou, Caixia;Zhang, Lin
肝血管生态位在肝纤维化的病理过程中起着重要作用。肝窦内皮细胞(LSECs)主要构成肝脏的血管壁龛。血管内皮细胞(EC)表达的鞘氨醇1-磷酸受体2(S1PR2)在血管功能调节中起重要作用。然而，目前尚不清楚肝脏LSEC-S1PR2是否可能调节病理性肝纤维化。本研究采用四氯化碳(CCl4)诱导大鼠肝纤维化模型。CCl4处理后，S1PR2在肝窦内皮细胞中的表达明显下调。LSECs中S1PR2的缺失明显减轻慢性损伤后的肝纤维化，而LSECs中S1PR2的过表达则加剧了肝纤维化的形成。体内实验进一步表明，LSECs中S1PR2的缺失抑制了肝星状细胞(HSC)的激活，而S1PR2在LSECs中的过表达增强了HSC的激活，并产生了更多的细胞外基质成分。在机制上，LSEC-S1PR2激活YAP信号通路，增强转化生长因子-β的反式激活，通过旁分泌的方式作用于HSC，从而加重肝纤维化。综上所述，我们的结果揭示了一种新的肝纤维化的病理机制，其中LSEC-S1PR2在调节肝纤维化的发展中发挥着重要作用，为未来抗肝纤维化的新的治疗靶点提供了新的靶点。
The hepatic vascular niche plays an important role in the pathological process of liver fibrosis. Liver sinusoidal endothelial cells (LSECs) predominantly compose hepatic vascular niches. Endothelial cell (EC)-expressing sphingosine 1-phosphate receptor 2 (S1pr2) plays an essential role in the regulation of vascular functions. Nevertheless, it remains unknown whether liver LSEC-S1pr2 might modulate pathological liver fibrosis. In this study, liver fibrosis was induced by hepatotoxin carbon tetrachloride (CCl4). The expression of S1pr2 is significantly downregulated in liver sinusoidal endothelial cells after CCl4 treatment. The loss of S1pr2 in LSECs significantly alleviated liver fibrosis after chronic insult, whereas the overexpression of S1pr2 in LSECs accentuated liver fibrogenesis. In vivo experiments further revealed that the deficiency of S1pr2 in LSECs dampened hepatic stellate cell (HSC) activation, while overexpression of S1pr2 in LSECs enhanced HSC activation with more extracellular matrix component production. Mechanistically, LSEC-S1pr2 activates the YAP signaling pathway to potentiate the transactivation of TGF-beta, which acts on HSCs in a paracrine manner, and thus aggravated liver fibrosis. Taken together, our results uncover a novel pathological mechanism of liver fibrosis in which LSEC-S1pr2 plays an important role in modulating the development of liver fibrosis, providing a future novel therapy target against liver fibrogenesis.