YAP contributes to liver injury through mediating capillarization of liver sinusoidal endothelial cells via GATA6/eNOS signaling
Junjun Wang, Zhenyang Shen, Guangwen Chen, Weiming Dai, Zhu Mei, Bo Shen, Yuecheng Guo, Jianxiang Wang, Hanjing Zhangdi, Qingqing Zhang, Jiaqi Gao, Qichao Ge, Hui Zhou, Hui Dong, Lungen Lu, Xiaobo Cai
Abstract
Capillarization of liver sinusoidal endothelial cells (LSECs) is a central event in response to liver injury. In this study, we investigated the role of Yes-associated protein 1 (YAP1, also known YAP) in LSEC capillarization and liver injury. YAP expression was assessed in liver samples from mice injured by CCl4 injection and DDC diet. EC-specific Yap1 conditional knockout mice (Yap1∆end) were generated by breeding Yap1fl/fl mice with Cdh5-CreERT2 mice. HA-PEI/siYap1 nanoparticles were applied to specifically inhibit YAP expression in LSECs. YAP was primarily expressed in LSECs, and its expression was elevated during liver fibrosis. EC-specific Yap1 deficiency significantly increased the fenestrae in LSECs and mitigated hepatocyte death and liver fibrosis. Overexpression of YAP in EC aggravated capillarization, hepatocyte death, and liver fibrosis. Mechanistically, YAP inhibited Gata6 transcription via binding to its promoter and thus resulted in LSEC capillarization. Overexpression of GATA6 in EC alleviated capillarization and liver fibrosis by activating Nos3 transcription. Moreover, specific delivery of HA-PEI-siYap1 nanoparticles to LSEC alleviated liver injury in mice. YAP-GATA6/eNOS signaling is essential in LSEC capillarization and subsequent hepatocyte death. Interventions targeting YAP in LSECs offer a promising strategy for the treatment of liver fibrosis. YAP expression in LSEC is upregulated in injured mice. Deletion/overexpression of Yap1 in LSECs attenuates/aggravates capillarization, hepatocyte death, and liver injury in mice, respectively. YAP inhibits Gata6 transcription via binding to its promoter and results in LSEC capillarization through GATA6/eNOS-dependent pathway. Delivering siYap1 to LSEC via nanoparticles represents a new approach for treating liver fibrosis.