Identification of key modules and driving genes in nonalcoholic fatty liver disease by weighted gene co-expression network analysis.

Background: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive liver fat deposition, and progresses to liver cirrhosis, and even hepatocellular carcinoma. However, the invasive diagnosis of NAFLD with histopathological evaluation remains risky. This study investigated potential genes correlated with NAFLD, which may serve as diagnostic biomarkers and even potential treatment targets.

Methods: The weighted gene co-expression network analysis (WGCNA) was constructed based on dataset E-MEXP-3291. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to evaluate the function of genes.

Results: Blue module was positively correlated, and turquoise module negatively correlated with the severity of NAFLD. Furthermore, 8 driving genes (ANXA9, FBXO2, ORAI3, NAGS, C/EBPα, CRYAA, GOLM1, TRIM14) were identified from the overlap of genes in blue module and GSE89632. And another 8 driving genes were identified from the overlap of turquoise module and GSE89632. Among these driving genes, C/EBPα (CCAAT/enhancer binding protein α) was the most notable. By validating the expression of C/EBPα in the liver of NAFLD mice using immunohistochemistry, we discovered a significant upregulation of C/EBPα protein in NAFLD.

Conclusion: we identified two modules and 16 driving genes associated with the progression of NAFLD, and confirmed the protein expression of C/EBPα, which had been paid little attention to in the context of NAFLD, in the present study. Our study will advance the understanding of NAFLD. Moreover, these driving genes may serve as biomarkers and therapeutic targets of NAFLD.