Abstract
Toxic liver injury causes necrosis and fibrosis, which may lead to cirrhosis and liver failure. Despite recent progress in understanding the mechanism of liver fibrosis, our knowledge of the molecular-level details of this disease is still incomplete. The elucidation of networks and pathways associated with liver fibrosis can provide insight into the underlying molecular mechanisms of the disease, as well as identify potential diagnostic or prognostic biomarkers. Towards this end, we analyzed rat gene expression data from a range of chemical exposures that produced observable periportal liver fibrosis as documented in DrugMatrix, a publicly available toxicogenomics database. We identified genes relevant to liver fibrosis using standard differential expression and co-expression analyses, and then used these genes in pathway enrichment and protein-protein interaction (PPI) network analyses. We identified a PPI network module associated with liver fibrosis that includes known liver fibrosis-relevant genes, such as tissue inhibitor of metalloproteinase-1, galectin-3, connective tissue growth factor, and lipocalin-2. We also identified several new genes, such as perilipin-3, legumain, and myocilin, which were associated with liver fibrosis. We further analyzed the expression pattern of the genes in the PPI network module across a wide range of 640 chemical exposure conditions in DrugMatrix and identified early indications of liver fibrosis for carbon tetrachloride and lipopolysaccharide exposures. Although it is well known that carbon tetrachloride and lipopolysaccharide can cause liver fibrosis, our network analysis was able to link these compounds to potential fibrotic damage before histopathological changes associated with liver fibrosis appeared. These results demonstrated that our approach is capable of identifying early-stage indicators of liver fibrosis and underscore its potential to aid in predictive toxicity, biomarker identification, and to generally identify disease-relevant pathways.
Highlights
Exposure to toxic chemicals can lead to liver injury through a variety of mechanisms, such as oxidative stress, the immune response, activation of apoptotic pathways, and necrosis [1]
We identified a protein-protein interaction (PPI) network module associated with liver fibrosis that includes known liver fibrosis-relevant genes like Timp1, Lgals3, Ctgf, and Lcn2, along with several new genes
External validation In order to further demonstrate the relevance of network module M5 in liver fibrosis, we evaluated the M5 genes in two external datasets (GSE13747 and GSE6929) from the Gene Expression Omnibus (GEO)
Summary
Exposure to toxic chemicals can lead to liver injury through a variety of mechanisms, such as oxidative stress, the immune response, activation of apoptotic pathways, and necrosis [1]. Liver fibrosis typically starts with apoptosis or necrosis of hepatocytes, which causes reactive oxygen species generation. This process leads to the release of inflammatory mediators and results in activation of hepatic stellate cells [3], the main ECM-producing cells in the liver. This activation of hepatic stellate cells is the key pathogenic mechanism of liver fibrosis [3,4,5,6]. Activated hepatic stellate cells lead to further inflammation and ECM generation, which results in the replacement of liver parenchymal cells with ECM [5]. Our understanding of the molecular mediators of liver fibrosis remains incomplete, and we are still in the process of identifying such mediators [7,8]
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