Characterization of transcriptional modules related to fibrosing-NAFLD progression

Sci Rep. 2017 Jul 6;7(1):4748. doi: 10.1038/s41598-017-05044-2.

Abstract

Based on the severity of liver fibrosis, low or high-risk profile of developing end-stage liver disease was present in nonalcoholic fatty liver disease (NAFLD). However, the mechanisms inducing transition from mild to advanced NAFLD are still elusive. We performed a system-level study on fibrosing-NAFLD by weighted gene co-expression network analysis (WGCNA) to identify significant modules in the network, and followed by functional and pathway enrichment analyses. Moreover, hub genes in the module were analyzed by network feature selection. As a result, fourteen distinct gene modules were identified, and seven modules showed significant associations with the status of NAFLD. Module preservation analysis confirmed that these modules can also be found in diverse independent datasets. After network feature analysis, the magenta module demonstrated a remarkably correlation with NAFLD fibrosis. The top hub genes with high connectivity or gene significance in the module were ultimately determined, including LUM, THBS2, FBN1 and EFEMP1. These genes were further verified in clinical samples. Finally, the potential regulators of magenta module were characterized. These findings highlighted a module and affiliated genes as playing important roles in the regulation of fibrosis in NAFLD, which may point to potential targets for therapeutic interventions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Biomarkers / metabolism
  • Computational Biology
  • Datasets as Topic
  • Disease Progression
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Fibrillin-1 / genetics
  • Fibrillin-1 / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Humans
  • Liver Cirrhosis / diagnosis
  • Liver Cirrhosis / genetics*
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / pathology
  • Lumican / genetics
  • Lumican / metabolism
  • Mice
  • Mice, Knockout
  • Non-alcoholic Fatty Liver Disease / diagnosis
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Thrombospondins / genetics
  • Thrombospondins / metabolism
  • Transcriptome*

Substances

  • Apolipoproteins E
  • Biomarkers
  • EFEMP1 protein, human
  • Extracellular Matrix Proteins
  • FBN1 protein, human
  • Fibrillin-1
  • LUM protein, human
  • Lumican
  • Thrombospondins
  • thrombospondin 2