Dataset Information

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl₄-Induced Liver Fibrosis.

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.

SUBMITTER: Mercado-Gomez M

PROVIDER: S-EPMC7729774 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Multi-Omics Integration Highlights the Role of Ubiquitination in CCl<sub>4</sub>-Induced Liver Fibrosis.

Mercado-Gómez Maria M Lopitz-Otsoa Fernando F Azkargorta Mikel M Serrano-Maciá Marina M Lachiondo-Ortega Sofia S Goikoetxea-Usandizaga Naroa N Rodríguez-Agudo Rubén R Fernández-Ramos David D Bizkarguenaga Maider M Juan Virginia Gutiérrez-de VG Lectez Benoît B Aloria Kerman K Arizmendi Jesus M JM Simon Jorge J Alonso Cristina C Lozano Juan J JJ Avila Matias A MA Banales Jesus M JM Marin Jose J G JJG Beraza Naiara N Mato José M JM Elortza Félix F Barrio Rosa R Sutherland James D JD Mayor Ugo U Martínez-Chantar María L ML Delgado Teresa C TC

International journal of molecular sciences 20201127 23

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<sub ...[more]

PMID: 33261190

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Project description:BackgroundRifaximin is a poorly absorbed broad-spectrum antibiotic used for hepatic encephalopathy. Although increased Lactobacillaceae and decreased Bacteroidetes abundance are characteristic of hepatic encephalopathy, rifaximin does not dramatically alter the stool microbiota. As the antimicrobial effect of rifaximin increases by micellization with bile acids, we hypothesized that rifaximin alters the microbiota in the duodenum and jejunum, where the levels of bile acids are abundant.Methods and resultsEight-week-old BALB/c mice were injected with carbon tetrachloride (CCl4) intraperitoneally for 12 weeks to induce liver fibrosis. The mice were grouped into the control (n = 9), CCl4 (n = 13), and rifaximin group in which mice were treated with rifaximin for two weeks after CCl4 administration (n = 13). We analyzed the microbiota of the duodenum, jejunum, ileum, cecum, and stool using 16S ribosomal RNA gene analysis. The content of Lactobacillaceae, the most abundant bacterial family in the duodenum and small intestine, increased in the CCl4 group, especially in the jejunum (median 67.0% vs 87.8%, p = 0.03). Rifaximin significantly decreased Lactobacillaceae content in the duodenum (median 79.4% vs 19.0%, p = 0.006) and jejunum (median 87.8% vs 61.3%, p = 0.03), but not in the ileum, cecum, and stool. Bacteroidetes abundance tended to decrease on CCl4 administration and increased following rifaximin treatment in the duodenum and jejunum. S24_7, the most abundant family in Bacteroidetes, demonstrated a significant inverse correlation with Lactobacillaceae (duodenum, r = - 0.61, p < 0.001; jejunum, r = - 0.72, p < 0.001). In the ileum, cecum, and stool, the effect of rifaximin on the microbiota was minimal, with changes within the same phylum. The percentage of bacterial families, such as Lactobacillaceae and S24_7 in the duodenum and small intestine, did not correlate with that in the stool.ConclusionsThe abundance of Lactobacillaceae increased in the jejunum of mice with CCl4-induced liver fibrosis, while rifaximin significantly reduced it in the duodenum and jejunum. Thus, rifaximin possibly exerts its effect by altering the duodenal and jejunal microbiota. Furthermore, changes in the duodenal and small intestinal microbiota were not associated with that of stool, suggesting that the analysis of stool microbiota is insufficient to evaluate upper intestinal microbiota.

Dataset Information

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl₄-Induced Liver Fibrosis.

Publications

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl<sub>4</sub>-Induced Liver Fibrosis.

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Dataset Information

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis.

Publications

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl<sub>4</sub>-Induced Liver Fibrosis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl₄-Induced Liver Fibrosis.