Multi-Omics Integration Highlights the Role of Ubiquitination in CCl 4 -Induced Liver Fibrosis

• Published in: International journal of molecular sciences 2020-11, Vol.21 (23)
• Main Authors: Mercado-Gómez, Maria, Lopitz-Otsoa, Fernando, Azkargorta, Mikel, Serrano-Maciá, Marina, Lachiondo-Ortega, Sofia, Goikoetxea-Usandizaga, Naroa, Rodríguez-Agudo, Rubén, Fernández-Ramos, David, Bizkarguenaga, Maider, Juan, Virginia Gutiérrez-de, Lectez, Benoît, Aloria, Kerman, Arizmendi, Jesus M, Simon, Jorge, Alonso, Cristina, Lozano, Juan J, Avila, Matias A, Banales, Jesus M, Marin, Jose J G, Beraza, Naiara, Mato, José M, Elortza, Félix, Barrio, Rosa, Sutherland, James D, Mayor, Ugo, Martínez-Chantar, María L, Delgado, Teresa C
• Format: Article
• Language: English
• Subjects: Animals; Carbon Tetrachloride; DNA Damage; DNA Repair; Genomics; Hep G2 Cells; Humans; Liver Cirrhosis - chemically induced; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Regeneration; Mice, Inbred C57BL; Proliferating Cell Nuclear Antigen - metabolism; Proteome - metabolism; Ubiquitination
• ISSN: 1422-0067
• DOI: 10.3390/ijms21239043

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl )-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process "protein polyubiquitination" is enriched after CCl -induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin ( Ub mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl -induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl -induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis.