Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis
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Date
2020-11-27Author
Mercado Gómez, María
Lopitz Otsoa, Fernando
Azkargorta, Mikel
Serrano Maciá, Marina
Lachiondo Ortega, Sofía
Goikoetxea Usandizaga, Naroa
Rodríguez Agudo, Rubén
Fernández Ramos, David
Bizkarguenaga, Maider
Gutiérrez de Juan, Virginia
Lectez, Benoit
Aloria Escolastico, Kerman
Simón Espinosa, Jorge
Alonso, Cristina
Lozano, Juan José
Marin, Jose J. G.
Beraza, Naiara
Mato, José M.
Elortza, Felix
Barrio Olano, María Rosa
Sutherland, James D.
Cardoso Delgado, Teresa de Jesús
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International Journal of Molecular Sciences 21(23) : (2020) // Article ID 9043
Abstract
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 (CCl4)-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 CCl4-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl4-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 CCl4-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.
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Except where otherwise noted, this item's license is described as 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
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