Multi-omics characterization of a diet-induced obese model of non-alcoholic steatohepatitis

Abstract

to improve the understanding of the complex biological processes underlying the development of non-alcoholic steatohepatitis (nASH), a multi-omics approach combining bulk RnA-sequencing based transcriptomics, quantitative proteomics and single-cell RnA-sequencing was used to characterize tissue biopsies from histologically validated diet-induced obese (Dio) nASH mice compared to chow-fed controls. Bulk RnA-sequencing and proteomics showed a clear distinction between phenotypes and a good correspondence between mRnA and protein level regulations, apart from specific regulatory events discovered by each technology. Transcriptomics-based gene set enrichment analysis revealed changes associated with key clinical manifestations of nASH, including impaired lipid metabolism, increased extracellular matrix formation/remodeling and pro-inflammatory responses, whereas proteomics-based gene set enrichment analysis pinpointed metabolic pathway perturbations. Integration with single-cell RNA-sequencing data identified key regulated cell types involved in development of nASH demonstrating the cellular heterogeneity and complexity of nASH pathogenesis. Non-alcoholic fatty liver disease (NALFD) comprises a wide spectrum of liver diseases ranging from typically benign steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis, that can progress into cirrhosis, hepatocellular carcinoma and ultimately end-stage liver disease 1-3. The development of NASH is driven by complex and dynamic molecular mechanisms, implicating multiple parallel signalling pathways. However, the interplay between these different clinical and molecular manifestations linked to progression of NAFLD into NASH is not fully understood. Currently, no pharmacological therapies for NASH exist, however lifestyle modifications have shown to be efficacious for NASH resolution 4. There are no early diagnostic endpoints known, and since hepatic steatosis and fibrosis can present itself as asymptomatic there is an unmet need to better understand the etiology and pathogenesis of NASH. Accordingly, several rodent models mimicking pathological features of NASH have been developed to accommodate this 5. Due to the distinct hepatic features of NASH, histological techniques based on qualitative scoring systems 6,7 and quantitative image analysis have been developed for research applications. Omics-based strategies have been instrumental for hypothesis-free analysis of molecular changes in NASH. For example, genome-wide association studies have identified several loci with variants showing increased risk of NAFLD and NASH development 8-11 or protection from more aggressive liver pathologies 12. Furthermore, transcriptomics has been successful in identifying novel regulatory mechanism in NASH pathogenesis 13-17. Despite the value of transcriptomics, these approaches will not always reflect the actual abundance at the protein level of a given the specific gene product in the cell 18 or extracellular space/surrounding body fluids 19. Quantitative proteomics has su...

Comparison of liver biopsies before and after direct-acting antiviral therapy for hepatitis C and correlation with clinical outcome

“…( 2 )” was more objectively calculated in these five study patients using a quantitative imaging software algorithm (Visiopharm), as described in the methods, “ Quantification of hepatic steatosis ” section (Fig. 3 E–H) and other studies 22 – 24 . Using this method, two of the patients (patients 2 and 10) had decreased steatosis (4.49- and 6.20-fold, respectively) and three patients (patients 4, 7, and 8) had increased steatosis (7.34-, 2.22-, and 3.26-fold, respectively) post-DAA treatment (Table 2 , Fig.…”

“…An interesting observation was the marked difference in the percentage of hepatic steatosis in the estimation made by the pathologist when compared to that determined using the Visiopharm algorithm. Visiopharm is an advanced imaging software platform that enables more precise quantification of various parameters such as fibrosis and steatosis in histology material 22 , 24 , 32 . Overall, the percentages estimated by the pathologist were much higher than those determined by the imaging software.…”

Western Diet Induced Remodelling of the Tongue Proteome

“…There is growing evidence that diet-induced obesity can alter the oral gustatory pathways, thus affecting nutritional intake and further exacerbating the condition [22,[36][37][38]. Though several system-wide studies have investigated the effects of HFD consumption on whole body metabolism, none have reported on any associated changes occurring in the orosensory pathways [39][40][41][42]. Therefore, in this study, we have performed the first in-depth characterisation of the mouse tongue proteome following chronic intake of a typical Western diet, enriched in dietary fats, complex sugars and cholesterol.…”

Next Generation Probiotics for Neutralizing Obesogenic Effects: Taxa Culturing Searching Strategies

“…As previously mentioned, microbiomics give us a great insight into the regulation of gut microbiota. However, in order to understand the complex biological pathways behind diseases, the identification of novel -omics biomarkers, such as identification of genes (genomics), gene expressions and phenotype (epigenomics), messenger RNA and micro RNA (transcriptomics), proteins (proteomics), and metabolites (metabolomics, lipidomics, glycomics) could bring forward knowledge on probiotics and their effects on obesity and its modulation of pathophysiological mechanisms that have links with chronic diseases [ 134 , 135 ].…”