基于生物信息学分析非酒精性脂肪肝疾病发展关键基因

Bioinformatics based analysis of key genes underlying the development of nonalcoholic fatty liver disease

目的基于生物信息学技术筛选非酒精性脂肪肝病(NAFLD)进展过程中的关键基因,并探讨其潜在生物学机制。方法通过整合基因表达公共数据库(GEO)中NAFLD相关测序数据集GSE135251和GSE167523,分析在单纯性非酒精性脂肪肝(NAFL)与非酒精性脂肪性肝炎(NASH)中差异表达的基因。对筛选得到的差异基因进行基因本体论(GO)功能富集分析,京都基因与基因组百科全书(KEGG)和Reactome信号通路分析。通过STRING数据库及Cytoscape3.7.2软件寻找关键基因并观察不同纤维化分级和不同活动度评分下关键基因的表达情况。此外,基于NAFLD小鼠的单细胞RNA-seq数据集,观察了关键基因在不同细胞簇的表达。结果通过生物信息学方法从两个数据集获得NAFLD的97个共同的差异基因,GO功能富集分析主要表现在细胞外基质组织。信号通路则主要为细胞外基质(ECM)-受体的相互作用。基于蛋白互作网络(PPI network)和Cytoscape软件确定5个关键基因:COL1A1、THBS2、CXCL8、THY1及LOXL1。关键基因的表达情况与纤维化分级及活动度评分呈明显正相关,表明其与NAFLD进展密切相关。这些关键基因主要在肝星状细胞(HSCs)和自然杀伤细胞/T淋巴细胞(NK/T cells)上高表达。结论本研究通过生物信息学技术筛选出5个可能参与NAFL向NASH转变的关键基因,细胞外基质-受体的相互作用信号通路可能是NAFLD进展的关键分子机制。

Objective To identify key genes and their potential biological mechanisms in the progression of non-alcoholic fatty liver disease(NAFLD)using bioinformatics technology.Methods Genes differentially expressed in simple non-alcoholic fatty liver disease(NAFL)and non-alcoholic steatohepatitis(NASH)were analyzed by integrating NAFLD-related sequencing datasets GSE135251 and GSE167523 from the Gene Expression Omnibus(GEO)datebase.Gene Ontology(GO)functional enrichment analysis,Kyoto Encyclopedia of Genes and Genomes(KEGG)and Reactome signaling pathway analysis were performed.Key genes were identified by STRING database and Cytoscape3.7.2 software,and the expression of key genes under different fibrosis grades and activity scores was observed.In addition,the expression of key genes in different cell clusters was observed based on the single-cell RNA-seq dataset of NAFLD mice.Results Bioinformatics methods were used to obtain 97 common differential genes in NAFLD from two datasets.GO functional enrichment analysis was mainly performed in Extracellular Matrix(ECM)tissues.The main signaling pathway is ECM-receptor interaction.Five key genes were identified based on PPI network and Cytoscape software:COL1A1,THBS2,CXCL8,THY1 and LOXL1.The expression of key genes was significantly positively correlated with fibrosis grade and activity score,indicating that they were closely related to the progression of NAFLD.These key genes are highly expressed in hepatic stellate cells(HSCs)and natural killer/T cells(NK/T cells).Conclusion In this study,bioinformatics technology was used to identify five key genes that may be involved in the NAFL-NASH transformation,suggesting that the ECM-receptor interaction signaling pathway may be a key molecular mechanism of NAFLD disease progression.