Comprehensive Analysis of NAFLD and the Therapeutic Target Identified.
Comprehensive Analysis of NAFLD and the Therapeutic Target Identified.
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NAFLD 综合分析及治疗靶点确定
DOI：
10.3389/fcell.2021.704704
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发表时间：
2021
影响因子：
5.5
通讯作者：
Chen H
中科院分区：
文献类型：
--
作者：
Wen W;Wu P;Zhang Y;Chen Z;Sun J;Chen H
目的：非酒精性脂肪性肝病（NAFLD）是世界范围内严重的健康威胁。本研究的目的是全面描述NAFLD的代谢和免疫学特征，并探索NAFLD潜在的治疗药物靶点。方法：从Gene Expression Omnibus （GEO）数据库下载6个NAFLD数据集，包括GSE48452、GSE63067、GSE66676、GSE89632、GSE24807和GSE37031。然后，我们使用这些数据集来识别和分析NAFLD患者和正常受试者样本中差异表达的基因，随后分析NAFLD患者的代谢和免疫特征。我们还使用连接图（CMAP）数据库确定了NAFLD的潜在治疗药物。此外，我们利用最小深度随机森林分析构建了预测模型，并筛选了潜在的治疗靶点。最后，在棕榈酸（PA）刺激的脂肪肝模型中验证了治疗靶点。结果：共获得1358个差异表达基因（differential expression genes, deg），主要富集于碳水化合物代谢、脂质代谢等代谢途径。免疫浸润分析显示，NAFLD记忆性B细胞、调节性T细胞和M1巨噬细胞显著上调，辅助滤泡性T细胞下调。这可能为NAFLD发病机制中免疫-代谢相互作用提供参考。通过CMAP数据库，地高辛和helveticoside被确定为NAFLD的潜在治疗药物。构建了基于最小深度随机森林分析的五基因预测模型，训练集和验证集的受试者工作特征（ROC）曲线均达到1。5个候选治疗靶点是ENO3、CXCL10、INHBE、LRRC31和OPTN。此外，敲除OPTN后肝细胞脂肪生成效率下降，证实了OPTN作为NAFLD新治疗靶点的潜力。结论：本研究为NAFLD的分子发病机制提供了更深入的认识。我们利用5个关键基因构建了具有较强预测效果的诊断模型。因此，这五个关键基因可能在NAFLD的诊断和治疗中发挥重要作用，特别是那些OPTN表达升高的NAFLD。
Objective: Non-alcoholic fatty liver disease (NAFLD) is a serious health threat worldwide. The aim of this study was to comprehensively describe the metabolic and immunologic characteristics of NAFLD, and to explore potential therapeutic drug targets for NAFLD. Methods: Six NAFLD datasets were downloaded from the Gene Expression Omnibus (GEO) database, including GSE48452, GSE63067, GSE66676, GSE89632, GSE24807, and GSE37031. The datasets we then used to identify and analyze genes that were differentially expressed in samples from patients with NAFLD and normal subjects, followed by analysis of the metabolic and immunologic characteristics of patients with NAFLD. We also identified potential therapeutic drugs for NAFLD using the Connectivity Map (CMAP) database. Moreover, we constructed a prediction model using minimum depth random forest analysis and screened for potential therapeutic targets. Finally, therapeutic targets were verified in a fatty liver model stimulated by palmitic acid (PA). Results: A total of 1,358 differentially expressed genes (DEGs) were obtained, which were mainly enriched in carbohydrate metabolism, lipid metabolism, and other metabolic pathways. Immune infiltration analysis showed that memory B cells, regulatory T cells and M1 macrophage were significantly up-regulated, while T cells follicular helper were down regulated in NAFLD. These may provide a reference for the immune-metabolism interaction in the pathogenesis of NAFLD. Digoxin and helveticoside were identified as potential therapeutic drugs for NAFLD via the CMAP database. In addition, a five-gene prediction model based on minimum depth random forest analysis was constructed, and the receiver operating characteristic (ROC) curves of both training and validation set reached 1. The five candidate therapeutic targets were ENO3, CXCL10, INHBE, LRRC31, and OPTN. Moreover, the efficiency of hepatocyte adipogenesis decreased after OPTN knockout, confirming the potential use of OPTN as a new therapeutic target for NAFLD. Conclusion: This study provides a deeper insight into the molecular pathogenesis of NAFLD. We used five key genes to construct a diagnostic model with a strong predictive effect. Therefore, these five key genes may play an important role in the diagnosis and treatment of NAFLD, particularly those with increased OPTN expression.
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影响因子：
82.9
作者：
Friedman SL;Neuschwander-Tetri BA;Rinella M;Sanyal AJ
通讯作者：
Sanyal AJ
影响因子：
24.5
作者：
Gjorgjieva, Monika;Sobolewski, Cyril;Foti, Michelangelo
通讯作者：
Foti, Michelangelo
DOI：
10.20960/nh.1317
发表时间：
2018-02-01
期刊：
Nutrición Hospitalaria
影响因子：
--
作者：
Ferraz-de-Assunção, Silvana-Neves;Amaral-Boa-Sorte, Ney-Christian;Rodrigues-Silva, Luciana
通讯作者：
Rodrigues-Silva, Luciana
影响因子：
29.4
作者：
Goldberg D;Ditah IC;Saeian K;Lalehzari M;Aronsohn A;Gorospe EC;Charlton M
通讯作者：
Charlton M
DOI：
10.1002/hep.28252
发表时间：
2016-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Ibrahim SH;Hirsova P;Tomita K;Bronk SF;Werneburg NW;Harrison SA;Goodfellow VS;Malhi H;Gores GJ
通讯作者：
Gores GJ