Abstract
Multifactorial metabolic diseases, such as non-alcoholic fatty liver disease, are a major burden to modern societies, and frequently present with no clearly defined molecular biomarkers. Herein we used system medicine approaches to decipher signatures of liver fibrosis in mouse models with malfunction in genes from unrelated biological pathways: cholesterol synthesis—Cyp51, notch signaling—Rbpj, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling—Ikbkg, and unknown lysosomal pathway—Glmp. Enrichment analyses of Kyoto Encyclopedia of Genes and Genomes (KEGG), Reactome and TRANScription FACtor (TRANSFAC) databases complemented with genome-scale metabolic modeling revealed fibrotic signatures highly similar to liver pathologies in humans. The diverse genetic models of liver fibrosis exposed a common transcriptional program with activated estrogen receptor alpha (ERα) signaling, and a network of interactions between regulators of lipid metabolism and transcription factors from cancer pathways and the 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 potentially, also sex. The discovered novel features of multifactorial liver fibrotic pathologies could aid also in improved stratification of other fibrosis related pathologies.
Highlights
Fibrosis is a common feature of skin, lung, kidney, and liver diseases; it can affect virtually every organ
We discovered that hepatocyte-specific Cyp51 knockout (LKO) males and females develop liver fibrosis due to blockage of cholesterol synthesis [10]
We focused on single gene knockouts that develop histologically confirmed liver fibrosis without additional dietary or chemical insults, preferably in both sexes, and with well annotated transcriptome data
Summary
Fibrosis is a common feature of skin, lung, kidney, and liver diseases; it can affect virtually every organ. It is characterized by excessive deposition of connective tissue components, which leads to tissue remodeling and organ malfunction. High mortality is associated with fibrotic diseases. The progress in development of anti-fibrotic drugs is slow, especially for individual fibrotic diseases where mechanisms are not clear. There is a need to unravel the core fibrotic pathways across different fibrotic diseases, as well as across the same type of fibrotic disease that can arise from a multitude of causes. In addition to common fibrotic programs, other factors influencing fibrotic disease susceptibility may be distinct, with disease-specific and organ-specific risk factors [1]
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