Systems level analysis and identification of pathways and networks associated with liver fibrosis

PLoS One. 2014 Nov 7;9(11):e112193. doi: 10.1371/journal.pone.0112193. eCollection 2014.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Connective Tissue Growth Factor / genetics
  • Connective Tissue Growth Factor / metabolism
  • Galectin 3 / genetics
  • Galectin 3 / metabolism
  • Gene Expression Regulation*
  • Gene Regulatory Networks
  • Humans
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Protein Interaction Maps*
  • Rats, Sprague-Dawley
  • Signal Transduction
  • Systems Biology
  • Tissue Inhibitor of Metalloproteinase-1 / genetics
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism
  • Transcriptome


  • Galectin 3
  • Tissue Inhibitor of Metalloproteinase-1
  • Connective Tissue Growth Factor

Grants and funding

The authors were supported by the Military Operational Medicine Research Program and the U.S. Army's Network Science Initiative, U.S. Army Medical Research and Materiel Command (USAMRMC,, Ft. Detrick, MD. This research was supported in part by an appointment to the Postgraduate Research Participation Program at the U.S. Army Center for Environmental Health Research (USACEHR, administered by the Oak Ridge Institute for Science and Education through an interagency agreement between the U.S. Department of Energy and USAMRMC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.