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

Xiao‐lin Liu,Yanan Ming,Jingyi Zhang,Xiaoyu Chen,M. Zeng,Y. Mao

Published 2017 in Experimental and Molecular Medicine

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. Genetic screening and bioinformatics allow researchers in China to uncover the key regulators in non-alcoholic fatty liver disease (NAFLD). Low-grade inflammatory conditions caused by a build-up of fat in the liver are known by the collective term NAFLD. Although early-stage NAFLD has few symptoms it can lead to serious conditions including extensive scarring and cancer if left untreated. Yimin Mao and co-workers at Shanghai Jiao Tong University used genetic screening and bioinformatics tools to search for common genes, metabolites and signalling pathways shared by three different NAFLD conditions. They used serum and tissue samples from rat models, and identified 96 genes that were altered in all three conditions compared with controls. The team identified a transcription factor and a small protein that are key regulators in NAFLD, triggering abnormal fatty acid responses and liver inflammation.

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