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

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 Notch inhibitors in NASH treatment, we applied two gamma‐secretase inhibitors—DAPT and LY3039478—in an MCD diet‐induced mouse model of NASH, and found that both inhibitors effectively ameliorated hepatic steatosis, inflammation, and liver fibrosis. Conclusions Endothelial‐specific Notch activation triggered LSEC maladaptation and exacerbated NASH phenotypes in an eNOS‐dependent manner. Genetic and pharmacological inhibition of Notch signaling effectively restored LSEC homeostasis and ameliorated NASH progression.