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

Abstract

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.

Emergent Properties of the HNF4α-PPARγ Network May Drive Consequent Phenotypic Plasticity in NAFLD

“…Multiple studies have shown the importance of various key regulators and genetic alterations for the development and the progression of NAFLD [67,68]. However, there are only a few attempts to analyze NAFLD from a systems biology perspective, i.e., decoding how these different regulators interact in the context of NAFLD [17,[69][70][71][72]. Thus, mechanism-based modeling studies are required to elucidate these mechanisms from a dynamical systems perspective.…”

Emergent properties of HNF4α-PPARγ network may drive consequent phenotypic plasticity in NAFLD

“…However, there are only a few attempts to analyze NAFLD from a systems biology perspective, i.e. decoding how these different regulators interact in the context of NAFLD [17,[62][63][64][65]. Thus, mechanismbased modeling studies are required to elucidate these mechanisms form a dynamical systems perspective.…”

“…Hepatocyte Nuclear Factor 1α (HNF1α) [16][17][18]. HNF4α is an established master regulator of induction and maintenance of the hepatic cell state [19,20].…”

Integrative analysis of blood and gut microbiota data suggests a non-alcoholic fatty liver disease (NAFLD)-related disorder in French SLAdd minipigs

“…First, the DE genes were processed using Ingenuity Pathway Analysis (IPA). Forty-six enriched pathways were found, 22 of which (or 47.8%) were related to NAFLD (Supplementary Table 5), like for example "adipogenesis", "sirtuin signalling", "mTOR signalling", "PI3K/Akt signalling", "B Cell receptor signalling", and "hepatic fibrosis" 13,14,26,27 .…”