Endothelial POFUT1 controls injury-induced liver fibrosis by repressing fibrinogen synthesis

作者：Shan He, Yuru Luo, Wangge Ma, X Y Wang, Chengrong Yan, Wenyang Hao, Fang Yuan, Hongyu Su, Baochang Lai, Junhui Liu, Ying Xiong, Ting Bai, Xiaoyong Ren, Enqi Liu, Hua Han, Yue Wu, Zuyi Yuan, Yidong Wang · 发表于：Journal of Hepatology · 年份：2024 · DOI：10.1016/j.jhep.2024.02.032 · 被引用次数：44 · 研究领域：Liver physiology and pathology、Liver Disease and Transplantation、Liver Disease Diagnosis and Treatment

BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS: Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS: POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was att...