Notch‐triggered maladaptation of liver sinusoidal endothelium aggravates nonalcoholic steatohepatitis through endothelial nitric oxide synthase

作者：Zhiqiang Fang, Bai Ruan, Jingjing Liu, Juanli Duan, Zhen‐Sheng Yue, Ping Song, Hao Xu, Jian Ding, Xu Chen, Guo‐Rui Dou, Lin Wang · 发表于：Hepatology · 年份：2022 · DOI：10.1002/hep.32332 · 被引用次数：88 · 研究领域：Liver physiology and pathology、Nitric Oxide and Endothelin Effects、Liver Disease Diagnosis and Treatment

BACKGROUND AND AIMS: Although NASH can lead to severe clinical consequences, including cirrhosis and hepatocellular carcinoma, no effective treatment is currently available for this disease. Increasing evidence indicates that LSECs play a critical role in NASH pathogenesis; however, the mechanisms involved in LSEC-mediated NASH remain to be fully elucidated. APPROACH AND RESULTS: In the current study, we found that LSEC homeostasis was disrupted and LSEC-specific gene profiles were altered in methionine-choline-deficient (MCD) diet-induced NASH mouse models. Importantly, Notch signaling was found to be activated in LSECs of NASH mice. To then investigate the role of endothelial Notch in NASH progression, we generated mouse lines with endothelial-specific Notch intracellular domain (NICD) overexpression or RBP-J knockout to respectively activate or inhibit Notch signaling in endothelial cells. Notably, endothelial-specific overexpression of the NICD accelerated LSEC maladaptation and aggravated NASH, whereas endothelial cell-specific inhibition of Notch signaling restored LSEC homeostasis and improved NASH phenotypes. Furthermore, we demonstrated that endothelial-specific Notch activation exacerbated NASH by inhibiting endothelial nitric oxide synthase (eNOS) transcription, whereas administration of the pharmacological eNOS activator YC-1 alleviated hepatic steatosis and lipid accumulation resulting from Notch activation. Finally, to explore the therapeutic potential of using ...