Wang Yang, Zhang Yifan, Li Yimin, Liu Yun, Liu Yulan
Department of Gastroenterology, Peking University People's Hospital, Beijing, China.
Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China.
Front Cell Dev Biol. 2022 Sep 21;10:946566. doi: 10.3389/fcell.2022.946566. eCollection 2022.
There has been emerging evidence that liver sinusoidal endothelial cells (LSECs) play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH). This study aims to figure out the signature of the gene expression profile of LSECs in NASH and to explore potential biomarkers related to damaged LSECs in NASH. Animal experiments were performed to demonstrate the significant structural damage of LSECs in the NASH model. To further understand the functional changes of these damaged LSECs in NASH, we used the public GEO database that contained microarray data for the gene expression of LSECs in NASH and normal mouse liver. Differentially expressed genes (DEGs) were analyzed, and further Gene Ontology (GO) enrichment analysis was performed to understand the functional changes. The hub genes were then identified and validated external GEO databases. There was significant structural damage to LSECs in the NASH model, accompanied by remarkable functional changes of LSECs with 174 DEGs (156 upregulated and 18 downregulated genes). The functions of these DEGs were mainly enriched in the inflammatory reactions and immune responses. Nine specifically expressed hub genes were identified. Among them, CCL4 and ITGAX showed the most significant correlation with NASH, with AUROC of 0.77 and 0.86, respectively. The protein-protein interaction network, mRNA-miRNA interaction network, and ceRNA network were further predicted. LSECs show significant structural damage and functional changes in NASH. The LSEC-related DEGs, such as CCL4 and ITGAX, might be promising biomarkers as well as potential treatment targets for NASH.
越来越多的证据表明，肝窦内皮细胞（LSECs）在非酒精性脂肪性肝炎（NASH）的发病机制中起重要作用。本研究旨在找出NASH中LSECs基因表达谱的特征，并探索与NASH中受损LSECs相关的潜在生物标志物。进行动物实验以证明NASH模型中LSECs的显著结构损伤。为了进一步了解这些受损LSECs在NASH中的功能变化，我们使用了公共的GEO数据库，该数据库包含NASH和正常小鼠肝脏中LSECs基因表达的微阵列数据。分析差异表达基因（DEGs），并进一步进行基因本体（GO）富集分析以了解功能变化。然后鉴定枢纽基因并在外部GEO数据库中进行验证。NASH模型中LSECs存在显著的结构损伤，同时LSECs伴有显著的功能变化，有174个DEGs（156个上调基因和18个下调基因）。这些DEGs的功能主要富集在炎症反应和免疫反应中。鉴定出9个特异性表达的枢纽基因。其中，CCL4和ITGAX与NASH的相关性最为显著，曲线下面积（AUROC）分别为0.77和0.86。进一步预测了蛋白质-蛋白质相互作用网络、mRNA- miRNA相互作用网络和ceRNA网络。LSECs在NASH中表现出显著的结构损伤和功能变化。与LSEC相关的DEGs，如CCL4和ITGAX，可能是有前景的生物标志物以及NASH的潜在治疗靶点。
