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

肝星状细胞 生物 Notch信号通路 癌症研究 基因敲除 纤维化 细胞生物学 信号转导 免疫学 内分泌学 病理 医学 细胞凋亡 生物化学
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
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:81 (1): 135-148 被引量:5
标识
DOI:10.1016/j.jhep.2024.02.032
摘要

Background & AimsNOTCH 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 LSECs-expressed POFUT1 in liver fibrosis.MethodsEndothelial-specific Pofut1 knockout mice were generated and subjected to experimental liver fibrosis by chronic carbon tetrachloride exposure or by 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-seq, qPCR, and Western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSECs cultures. Liver single-cell RNA-seq data sets from cirrhotic patients and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies.ResultsPOFUT1 loss promoted injury-induced LSECs capillarization and HSC activation, leading to aggravated liver fibrosis. RNA-seq analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of cirrhotic patients. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to treatment with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling.ConclusionsEndothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen which function as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/NOTCH/HES1/STAT3/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases.
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