Multi-Omics Integration Highlights the Role of Ubiquitination in CCl4-Induced Liver Fibrosis.
Maria Mercado-GómezFernando Lopitz-OtsoaMikel AzkargortaMarina Serrano-MaciáSofia Lachiondo-OrtegaNaroa Goikoetxea-UsandizagaRubén Rodríguez-AgudoDavid Fernández-RamosMaider BizkarguenagaVirginia Gutiérrez-de JuanBenoît LectezKerman AloriaJesus M ArizmendiJorge SimonCristina AlonsoJuan J LozanoMatias A AvilaJesus M BanalesJose J G MarinNaiara BerazaJosé M MatoFélix ElortzaRosa BarrioJames D SutherlandUgo MayorMaría Luz Martínez-ChantarTeresa Cardoso DelgadoPublished in: International journal of molecular sciences (2020)
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.
Keyphrases
- liver fibrosis
- high glucose
- mass spectrometry
- diabetic rats
- dna repair
- drug induced
- dna damage response
- mouse model
- liver injury
- single cell
- extracellular matrix
- mental health
- oxidative stress
- small molecule
- emergency department
- type diabetes
- high resolution
- electronic health record
- ms ms
- insulin resistance
- weight gain
- physical activity
- liquid chromatography
- adipose tissue
- cell proliferation
- transcription factor
- high throughput
- big data
- simultaneous determination
- genome wide analysis