Exp Mol Med.  2017 Jan;49(1):e283. 10.1038/emm.2016.123.

Gene-metabolite network analysis in different nonalcoholic fatty liver disease phenotypes

• Liu XL
• Ming YN
• Zhang JY
• Chen XY
• Zeng MD
• Mao YM

• KMID: 2367529
• DOI: http://doi.org/10.1038/emm.2016.123

Abstract

We sought to identify common key regulators and build a gene-metabolite network in different nonalcoholic fatty liver disease (NAFLD) phenotypes. We used a high-fat diet (HFD), a methionine-choline-deficient diet (MCDD) and streptozocin (STZ) to establish nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NAFL+type 2 diabetes mellitus (T2DM) in rat models, respectively. Transcriptomics and metabolomics analyses were performed in rat livers and serum. A functional network-based regulation model was constructed using Cytoscape with information derived from transcriptomics and metabolomics. The results revealed that 96 genes, 17 liver metabolites and 4 serum metabolites consistently changed in different NAFLD phenotypes (>2-fold, P<0.05). Gene-metabolite network analysis identified ccl2 and jun as hubs with the largest connections to other genes, which were mainly involved in tumor necrosis factor, P53, nuclear factor-kappa B, chemokine, peroxisome proliferator activated receptor and Toll-like receptor signaling pathways. The specifically regulated genes and metabolites in different NAFLD phenotypes constructed their own networks, which were mainly involved in the lipid and fatty acid metabolism in HFD models, the inflammatory and immune response in MCDD models, and the AMPK signaling pathway and response to insulin in HFD+STZ models. Our study identified networks showing the general and specific characteristics in different NAFLD phenotypes, complementing the genetic and metabolic features in NAFLD with hepatic and extra-hepatic manifestations.

MeSH Terms

AMP-Activated Protein Kinases
Animals
Complement System Proteins
Diabetes Mellitus
Diet
Diet, High-Fat
Insulin
Liver
Metabolism
Metabolomics
Models, Animal
Non-alcoholic Fatty Liver Disease*
Peroxisomes
Phenotype
Rats
Streptozocin
Toll-Like Receptors
Tumor Necrosis Factor-alpha
AMP-Activated Protein Kinases
Complement System Proteins
Insulin
Streptozocin
Toll-Like Receptors
Tumor Necrosis Factor-alpha