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

• Published in: The FASEB journal Vol. 37; no. 5; pp. e22905 - n/a
• Main Authors: Liao, Yang, Zhou, Caixia, Duan, Yunhao, Liu, Xiuxiang, Yue, Jinnan, Li, Xiufen, Wu, Jinjin, Wan, Chaomin, Zhang, Lin
• Format: Journal Article
• Language: English
• Published: United States 01.05.2023
• Subjects: Endothelial Cells - metabolism; Humans; Liver Cirrhosis - metabolism; liver fibrosis; liver sinusoidal endothelial cells; Signal Transduction; sphingosine 1‐phosphate receptor 2 (S1pr2); Sphingosine-1-Phosphate Receptors - metabolism; Transforming Growth Factor beta - metabolism; sphingosine 1-phosphate receptor 2 (S1pr2); liver fibrosis; liver sinusoidal endothelial cells
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202201954R

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. Liver sinusoidal endothelial cells play pivotal roles in liver function and influences the development of liver fibrosis. This study revealed the molecular mechanism by which liver sinusoidal endothelial cells tightly controlled liver fibrosis progression. That is, liver sinusoidal endothelial cells express an important receptor, sphingosine 1‐ phosphate receptor 2 (S1pr2), which activates the Yap signaling pathway to upregulate the expression of TGF‐β, and thus influences the development of liver fibrosis. This finding provides a novel therapeutic target against liver fibrosis.