Systematic integrative analysis of gene expression identifies HNF4A as the central gene in pathogenesis of non-alcoholic steatohepatitis

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the Western world, and encompasses a spectrum from simple steatosis to steatohepatitis (NASH). There is currently no approved pharmacologic therapy against NASH, partly due to an incomplete understanding of its molecular basis. The goal of this study was to determine the key differentially expressed genes (DEGs), as well as those genes and pathways central to its pathogenesis. We performed an integrative computational analysis of publicly available gene expression data in NASH from GEO (GSE17470, GSE24807, GSE37031, GSE89632). The DEGs were identified using GEOquery, and only the genes present in at least three of the studies, to a total of 190 DEGs, were considered for further analyses. The pathways, networks, molecular interactions, functional analyses were generated through the use of Ingenuity Pathway Analysis (IPA). For selected networks, we computed the centrality using igraph package in R. Among the statistically significant predicted networks (p-val < 0.05), three were of most biological interest: the first is involved in antimicrobial response, inflammatory response and immunological disease, the second in cancer, organismal injury and development and the third in metabolic diseases. We discovered that HNF4A is the central gene in the network of NASH connected to metabolic diseases and that it regulates HNF1A, an additional transcription regulator also involved in lipid metabolism. Therefore, we show, for the first time to our knowledge, that HNF4A is central to the pathogenesis of NASH. This adds to previous literature demonstrating that HNF4A regulates the transcription of genes involved in the progression of NAFLD, and that HNF4A genetic variants play a potential role in NASH progression.