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.

New phthalimide analog ameliorates CCl4 induced hepatic injury in mice via reducing ROS formation, inflammation, and apoptosis

“…The results revealed that both PCNA and VEGF levels were elevated in the liver tissues of mice injected with CCl 4 compared to normal mice. These outcomes are consistent with the previous published studies ( Huang et al, 2018 , Rahmani et al, 2019 , Mercado-Gómez et al, 2020 ). On the other hand, the increased levels of PCNA and VEGF were normalized after the treatment with the phthalimide analog.…”

Effect of Short-Term Tacrolimus Exposure on Rat Liver: An Insight into Serum Antioxidant Status, Liver Lipid Peroxidation, and Inflammation

“…Several factors, such as hypoxia, pathological injury, and cell proliferation via the NOD-like receptor inflammasome pathway, contribute to increased expression of PCNA and CK-7 in the liver [ 38 – 41 ]. Increased expression of CK-7 and PCNA has been reported in liver transplant patients due to recurrence of liver complications, drug toxicity-induced hypoxia, and liver fibrosis [ 42 – 44 ]. Increased expression of PCNA and CK-7 in current findings may imply liver injury associated with dysregulation of antioxidants and lipid peroxidation.…”

Repeated toxic injuries of murine liver are tolerated through microsteatosis and mild inflammation

“…TGF-β (Friedmann, 2008). Maintaining quiescence and activation of HSC is a highly dynamic and complex process (Krizhanovsky et al 2008; Kisseleva et al 2012; Mercado-Gómez et al 2020). Accordingly, the progression and regression of liver disease in response to repetitive injuries at the patient’s level are also highly variable (Bedossa et al 2003; Sun et al 2020).…”

“…Using only a single level of measurement, e.g., transcriptomics or histopathology, limits the detection of possible alterations to one type, and thus captures changes only for a small subset of possible components interacting and steering the disease progression (Ogris et al 2021). To obtain a holistic view and reduce the single-level technical effects, studies utilizing multiple omic measurements are employed to support findings or identify targetable molecules in a specific disease context (Mardinoglu et al 2018; Mercado-Gómez et al 2020). Approaches using multi-level analysis outperform single-level analysis, as those are limited in their information content to one level and therefore may lead to missing and misinterpreted results (Domenico et al 2015, Schmitt et al 2013).…”