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.
Highlights
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disease, progressing from simple steatosis, to non-alcoholic steatohepatitis (NASH) with subsequent risks of developing NASH cirrhosis, and hepatocellular carcinoma[1]
Studies have reported a prevalence of NAFLD ranging from 10 to 46% in the United States, and biopsy-based studies have documented the presence of NASH in 3–5%[3, 4]
NASH is clearly a multifaceted disorder, with multiple genes and pathways contributing to its development
Summary
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver disease, progressing from simple steatosis, to non-alcoholic steatohepatitis (NASH) with subsequent risks of developing NASH cirrhosis, and hepatocellular carcinoma[1]. Studies have reported a prevalence of NAFLD ranging from 10 to 46% in the United States, and biopsy-based studies have documented the presence of NASH in 3–5%[3, 4]. The diagnosis of NASH is suspected based on the presence of metabolic risk factors, steatosis on ultrasound, and elevated transaminases, in the absence of any other etiology of liver disease[7]. It is confirmed through liver biopsy demonstrating characteristic features of steatosis, ballooning, and lobular inflammation. Given the increasing burden of disease, there is a clear need for biomarkers to detect disease at an earlier stage, as well as identification of more optimal therapeutic agents
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