A serum-induced gene signature in hepatocytes is associated with pediatric nonalcoholic fatty liver disease

ObjectivePediatric nonalcoholic fatty liver disease (NAFLD) is a growing problem, but its underlying mechanisms are poorly understood. We used transcriptomic reporter cell assays to investigate differences in transcriptional signatures induced in hepatocyte reporter cells by the sera of children with and without NAFLD.MethodsWe studied serum samples from 45 children with NAFLD and 28 children without NAFLD. The sera were used to induce gene expression in cultured HepaRG cells and RNA-sequencing was used to determine gene expression. Computational techniques were used to compare gene expression patterns.ResultsSera from children with NAFLD induced the expression of 195 genes that were significantly differentially expressed in hepatocytes compared to controls with obesity. NAFLD was associated with increased expression of genes promoting inflammation, collagen synthesis, and extracellular matrix remodeling. Additionally, there was lower expression of genes involved in endobiotic and xenobiotic metabolism, and downregulation of peroxisome function, oxidative phosphorylation, and xenobiotic, bile acid, and fatty acid metabolism. A 13-gene signature, including upregulation of TREM1 and MMP1 and downregulation of CYP2C9, was consistently associated with all diagnostic categories of pediatric NAFLD.ConclusionThe extracellular milieu of sera from children with NAFLD induced specific gene profiles distinguishable by a hepatocyte reporter system. Circulating factors may contribute to inflammation and extracellular matrix remodeling and impair xenobiotic and endobiotic metabolism in pediatric NAFLD. What is Known Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in children in the United States. Children with NAFLD are at risk for end-stage liver disease, liver failure and comorbid conditions. By responding to circulating factors, transcriptomic reporter cell assays have improved the understanding of different diseases.What is New Compared to control children with obesity, sera from children with NAFLD induces transcriptional changes in cultured hepatocytes that favor inflammation and extracellular matrix remodeling, and inhibition of endobiotic and xenobiotic metabolism. A 13-gene signature is consistently associated with pediatric NAFLD and contributes to prediction of histological features of disease.