Up-regulation of FUT8 inhibits TGF-β1-induced activation of hepatic stellate cells during liver fibrogenesis
Up-regulation of FUT8 inhibits TGF-β1-induced activation of hepatic stellate cells during liver fibrogenesis
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FUT8 上调抑制 TGF-β1 诱导的肝纤维化过程中肝星状细胞的活化
DOI：
10.1007/s10719-021-09975-x
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发表时间：
2021
影响因子：
3
通讯作者：
Ruan Yuanyuan
中科院分区：
文献类型：
--
作者：
Kuang Mengzhen;Wu Hao;Hu Lan;Guo Xinying;He Daochuan;Liu Bo;Chen Mengqian;Gu Jie;Gu Jianxin;Zeng Xiaoqing;Ruan Yuanyuan
肝纤维化是由慢性肝损伤引起的持续创伤愈合反应，肝星状细胞（hepatic stellate cells，HSCs）的活化被认为是肝纤维化的主要事件。FUT 8催化的核心岩藻糖基化是指在N-连接寡糖的最内层GlcNAc残基上添加岩藻糖基，参与细胞分化、迁移和信号转导等多种生物学过程。核心岩藻糖基化异常与多种疾病相关，包括心血管疾病、肿瘤和神经炎症，但在肝纤维化中了解较少。在此，我们从GEO数据库中证实FUT 8 mRNA水平在肝纤维化患者中升高，并与纤维化进展呈正相关。TAA诱导的小鼠肝纤维化模型中FUT 8的表达和核心岩藻糖基化水平也明显升高，主要分布在小鼠肝纤维间隔。TGF-β1作为最具促纤维化作用的细胞因子，在体外可促进HSC FUT 8的表达和总核心岩藻糖基化水平。然而，FUT 8的上调反过来又抑制了TGF-β1诱导的HSC转分化、迁移和促纤维化信号通路。结论：FUT 8的上调可能通过负反馈机制抑制TGF-β1诱导的HSC活化，为FUT 8靶向治疗肝纤维化提供了新的思路。
Liver fibrosis is a continuous wound healing response caused by chronic liver injury, and the activation of hepatic stellate cells (HSCs) is considered as the main event for it. Core fucosylation catalyzed by FUT8 refers to adding the fucosyl moiety to the innermost GlcNAc residue of N-linked oligosaccharides and is involved in many biological processes such as cell differentiation, migration, and signaling transduction. Aberrant core fucosylation is associated with a variety of diseases including cardiovascular disease, tumors and neuroinflammation, but much less is understood in liver fibrosis. Herein, we reportedFUT8mRNA level was increased in patients with liver fibrosis from GEO database and positively correlated with fibrosis progression. FUT8 expression and the core fucosylation were also elevated in TAA-induced mouse liver fibrosis model, and were mainly distributed in the fibrous septum of mouse liver. TGF-β1, as the most pro-fibrogenic cytokine, could promote the expression of FUT8 and total core fucosylation levels in HSCsin vitro. However, up-regulation of FUT8 in turn inhibited TGF-β1-induced trans-differentiation, migration and pro-fibrogenic signaling pathways in HSCs. In conclusion, our results suggest that the up-regulation of FUT8 inhibits TGF-β1-induced HSC activation in a negative feedback loop, and provide potential new therapeutic strategy for liver fibrosis by targeting FUT8.