Common transcriptional programme of liver fibrosis in mouse genetic models and humans

Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden of modern societies and frequently present with no clearly defined molecular biomarkers. Herein we used systems medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways. Enrichment analyses of KEGG, Reactome and TRANSFAC databases complemented with genome-scale metabolic modelling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional programme with activated ERα signalling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and immune system. The novel hallmarks of fibrosis are downregulated lipid pathways, including fatty acid, bile acid, and steroid hormone metabolism. Moreover, distinct metabolic subtypes of liver fibrosis were proposed, supported by unique enrichment of transcription factors based on the type of insult, disease stage, or sex.