Aisha Israr,1,*
1. Department of Medical Sciences, Shahrood Branch, Islamic Azad University, Shahrood, Iran.
Introduction: Nonalcoholic steatohepatitis (NASH) explains the inflammatory form of NAFLD and is considered to be the hepatic manifestation of metabolic syndrome. Improvement of therapeutic outcomes of NASH may be best achieved by targeting significant pathologic pathways. However, the molecular mechanisms of NASH are still not well understood. The present study aimed to explore hub genes and key pathways in NASH using computational bioinformatics approach.
Methods: To identify the candidate genes, microarray dataset GSE164760 was downloaded from Gene Expression Omnibus (GEO) database, which including 74 NASH samples and 6 healthy samples. The differentially expressed genes (DEGs) were identified using R studio software. The protein-protein interaction network (PPI) was constructed using Search Tool for the Retrieval of Interacting Genes (STRING; http://string-db.org) online database. Degree and Betweenness centrality were determined using Gephi software. Pathway enrichment analysis was performed through Enrichr web server.
Results: A total of 5467 DEGs were identified (adjective p-Value<0.05). Eighty one downregulated genes(logFC<-1) and 466 upregulated genes(logFC>1) were analyzed. Four hub upregulated genes were with degree more than 20 and betweenness centrality>500. These include MDM2, KAT2B, RAB7A and HNRNPC. MDM2 was with the highest betweenness. KEGG pathway analysis revealed that upregulated key genes were mainly enriched in Ubiquitin mediated proteolysis(MDM2, Combined Score= 505.1), p53 signaling pathway(MDM2, Combined Score= 227.3), Endocytosis(RAB7A, Combined Score= 419.8), Autophagy(RAB7A, Combined Score= 298.5), Notch signaling pathway(KAT2B, Combined Score=134.7) and Spliceosome(HNRNPC, Combined Score= 171.4). Moreover, three hub downregulated genes were with degree more than 10. These included JUN, FOS and DUSP1. JUN was with the highest betweenness. KEGG pathway analysis revealed that downregulated key genes were mainly enriched in apoptosis(JUN, Combined Score= 1361.5) and MAPK signaling pathway(FOS and DUSP1, Combined Score= 599.3).
Conclusion: Hub genes and pathways identified in the present study help us understand the molecular mechanisms underlying NASH, and provide candidate targets for diagnosis and treatment of NASH.