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Common Transcriptional Program of Liver Fibrosis in Mouse Genetic Models and Humans
Kaja Blagotinšek Cokan1, Žiga Urlep1, Miha Moškon2
1Centre for Functional Genomics and Bio-Chips, Institute of Biochemistry and Molecular Genetics, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia.
International Journal of Molecular Sciences
|January 20, 2021
Summary
Researchers identified common molecular signatures in mouse models of liver fibrosis, revealing activated estrogen receptor alpha signaling and altered lipid metabolism. These findings could improve disease stratification and biomarker discovery for multifactorial liver diseases.
Area of Science:
- Biochemistry
- Systems Biology
- Genomics
Background:
- Multifactorial metabolic diseases like non-alcoholic fatty liver disease lack clear molecular biomarkers.
- Liver fibrosis is a significant health burden with complex underlying mechanisms.
Purpose of the Study:
- To decipher molecular signatures of liver fibrosis using system medicine approaches in genetically diverse mouse models.
- To identify commonalities and differences in fibrotic pathways across various genetic insults.
Main Methods:
- Utilized system medicine approaches on mouse models with genetic defects in cholesterol synthesis (Cyp51), Notch signaling (Rbpj), NF-κB signaling (Ikbkg), and a lysosomal pathway (Glmp).
- Performed enrichment analyses using KEGG, Reactome, and TRANSFAC databases.
- Employed genome-scale metabolic modeling to analyze fibrotic signatures.
Main Results:
- Identified conserved fibrotic signatures across diverse genetic models, mirroring human liver pathologies.
- Revealed a common transcriptional program involving activated estrogen receptor alpha (ERα) signaling.
- Discovered downregulated lipid metabolism pathways (fatty acid, bile acid, steroid hormone) as novel hallmarks of fibrosis.
- Proposed distinct metabolic subtypes of liver fibrosis based on genetic insult, disease stage, and sex.
Conclusions:
- The study identified novel molecular features and metabolic subtypes of liver fibrosis.
- Findings suggest activated ERα signaling and altered lipid metabolism are central to fibrosis development.
- These discoveries may facilitate improved stratification and biomarker identification for liver fibrosis and other fibrotic diseases.
