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.
Highlights
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH).[1]
The NASH group had 10- and 5-fold increased serum alanine aminotransferase and aspartate aminotransferase levels, and both high-fat diet (HFD) and HFD+STZ groups had a 4- and 6-fold increased homeostasis model assessment of insulin resistance (HOMA-IR) levels, respectively (Po0.05; Table 1). These results indicated that HFD, methionine-choline-deficient diet (MCDD) and HFD+STZ rat models were all successfully established, with more severe liver injury found in the MCDD group and advanced metabolic disorders noted in the HFD+STZ group
Analysis of hepatic genes commonly altered in different NAFLD phenotypes According to our defined filtering criteria, we identified 205, 1794 and 208 genes that were upregulated and 155, 827 and 211 genes that were downregulated in HFD, MCDD and HFD +STZ groups, respectively, compared with the control group (Po0.05; Supplementary Tables S1–S3)
Summary
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of diseases ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH).[1]. Recent studies have shown that cardiovascular disease (30%) and extra-hepatic malignancy (28%) are the most common causes of death in patients with NAFLD rather than liver disease (19%).[4] more attention should be paid to the cardiovascular metabolic risk in NAFLD. The combination of transcriptomics and metabolomics is often preferred as a powerful tool in the study of multisystem diseases such as NAFLD.[5] Several studies have identified regulated genes and pathways in NAFLD, including stearoyl-coenzyme A desaturase 1 (Scd1), sterol regulatory element binding factor 1c (Srebf1c) and the disturbances of phospholipid and bile acid metabolism.[6,7] these studies focused exclusively on one NAFLD phenotype (that is, NAFL or NASH) without taking extra-hepatic manifestations of NAFLD into account
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