肝窦内皮S1pr2通过YAP/TGF-β信号通路调控实验性肝纤维化,The FASEB Journal

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肝窦内皮S1pr2通过YAP/TGF-β信号通路调控实验性肝纤维化
The FASEB Journal ( IF 4.4 ) Pub Date : 2023-04-11 , DOI: 10.1096/fj.202201954r
Yang Liao _{1,

2,

3} , Caixia Zhou ₄ , Yunhao Duan ₄ , Xiuxiang Liu ₄ , Jinnan Yue ₄ , Xiufen Li ₂ , Jinjin Wu ₅ , Chaomin Wan _{1,

3,

6} , Lin Zhang ₄

Affiliation

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 (LSEC) 主要构成肝血管壁龛。表达内皮细胞 (EC) 的鞘氨醇 1-磷酸受体 2 (S1pr2) 在血管功能的调节中起着重要作用。尽管如此，肝脏 LSEC-S1pr2 是否可能调节病理性肝纤维化仍然未知。在这项研究中，肝纤维化是由肝毒素四氯化碳 (CCl ₄ ) 诱导的。_{CCl 4}后肝窦内皮细胞S1pr2的表达显着下调治疗。LSEC 中 S1pr2 的缺失显着减轻了慢性损伤后的肝纤维化，而 LSEC 中 S1pr2 的过表达加剧了肝纤维化。体内实验进一步表明，LSEC 中 S1pr2 的缺乏抑制了肝星状细胞 (HSC) 的激活，而 LSEC 中 S1pr2 的过表达增强了 HSC 的激活，产生了更多的细胞外基质成分。从机制上讲，LSEC-S1pr2 激活 YAP 信号通路以增强 TGF-β 的反式激活，后者以旁分泌方式作用于 HSC，从而加重肝纤维化。综上所述，我们的研究结果揭示了一种新的肝纤维化病理机制，其中 LSEC-S1pr2 在调节肝纤维化的发展中发挥重要作用，为未来抗肝纤维化提供了新的治疗靶点。

"点击查看英文标题和摘要"

Liver sinusoidal endothelial S1pr2 regulates experimental liver fibrosis through YAP/TGF-β signaling pathway

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-β, 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.

更新日期：2023-04-11

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