Comprehensive Analysis of NAFLD and the Therapeutic Target Identified

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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