Hepatic gene expression and functional changes associated with nonalcoholic steatohepatitis

Non-alcoholic steatohepatitis (NASH) is a pathological condition of the liver in which hepatocyte steatosis, invasion of inflammatory cells and hepatic injury occur without alcohol abuse. Despite the known risk of liver cancer and liver fibrosis that may progress to liver cirrhosis that exists with NASH, an understanding of related gene expression and associated functional changes remains insufficient. The present study used a mouse model of NASH induced by a high-fat diet to examine gene expression in the liver and to search for transcripts that could predict early liver fibrosis in the future. Mice fed a high-fat diet for 2 weeks showed typical NASH liver histology by hematoxylin and eosin staining, and increased fibrosis was confirmed by Sirius red staining after 6 weeks. Functional changes associated with liver damage, liver inflammation, liver steatosis and liver fibrosis were predicted by toxicological ontology analysis using Ingenuity Pathways Analysis. Downregulated microRNA (miR)-21 and upregulated collagen type III α1 mRNA in the liver and upregulated exosomal miR-21 in serum of mice fed a high-fat diet for 1 and/or 2 weeks were confirmed by reverse transcription-quantitative PCR, suggesting that these changes occur prior to histological confirmation of fibrosis. Therefore, it may be possible to predict future liver fibrosis by analyzing fibrosis-related genes that shift prior to pathological findings.