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Deconvolution of cell types from bulk gene expression profiling in a nonalcoholic steatohepatitis model of mice liver reveals global alteration of macrophages and hepatic stellate cells

ABSTRACT: Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease due to the accumulation of excess fat in the liver cells. The two histological categories of NAFLD are NASH (nonalcoholic steatohepatitis) and NAFL (nonalcoholic fatty liver). While NASH is typically considered a disorder of the hepatocytes, the role of other liver cell types in its pathophysiology and progression is becoming more established. Bioinformatics analytic approaches can now incorporate single cell RNA transcriptomics (sc-RNA-Seq) as a reference to deconvolute cell type profiles and proportions in bulk /RNA-Seq data. This technique can be inferred to investigate the changes in cellular compositions in tissues across multiple disease states. This study performed deconvolution analysis using CIBERSORTx, by integrating the bulk/RNA-Seq data with single-cell transcriptomic data to identify changes in cell composition associated with NASH. This study aimed to observe the changes in cell types among healthy and NASH mouse liver. The result of the analyses revealed a general increase in the fraction of HSC (Hepatic Stellate cells), liver macrophages, and cholangiocytes in NASH samples. Hepatocytes had a higher proportion in healthy samples compared with NASH, however, no significant observable difference was established in the endothelial cell proportions. We gained insight on the cell-type proportions profiles of NASH mice models, which highly mimics the human NASH.

ORGANISM(S): Mus musculus

PROVIDER: GSE206338 | GEO | 2024/12/31

REPOSITORIES: GEO

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Project description:Objective: Nonalcoholic fatty liver disease (NAFLD) is linked to obesity and diabetes, suggesting an important role of adipose tissue in the pathogenesis of NAFLD. Here we aim to investigate the interaction between adipose tissue and liver in NAFLD, and identify potential early plasma markers that predict NASH. Research Design and Methods: C57Bl/6 mice were chronically fed a high fat diet to induce NAFLD and compared with mice fed low fat diet. Extensive histological and phenotypical analyses coupled with a time-course study of plasma proteins using multiplex assay was performed. Results: Mice exhibited pronounced heterogeneity in liver histological scoring, leading to classification into 4 subgroups: LF-low (LFL) responders displaying normal liver morphology, LF-high (LFH) responders showing benign hepatic steatosis, HF-low (HFL) responders displaying pre-NASH with macrovesicular lipid droplets, and HF-high (HFH) responders exhibiting overt NASH characterized by ballooning of hepatocytes, presence of Mallory bodies, and activated inflammatory cells. Compared to HFL responders, HFH mice gained weight more rapidly and exhibited adipose tissue dysfunction characterized by decreased final fat mass, enhanced macrophage infiltration and inflammation, and adipose tissue remodelling. Plasma haptoglobin, IL-1β, TIMP-1, adiponectin and leptin were significantly changed in HFH mice. Multivariate analysis indicated that in addition to leptin, plasma CRP, haptoglobin, eotaxin and MIP-1α early in the intervention were positively associated with liver triglycerides. Intermediate prognostic markers of liver triglycerides included IL-18, IL-1β, MIP-1γ and MIP-2, whereas insulin, TIMP-1, GCP-2 and MPO emerged as late markers. Conclusions: Our data support the existence of a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. Keywords: Expression profiling by array Male wildtype C57Bl/6 mice were fed LFD or HFD for 21 weeks. Mice were divided into 4 groups based on liver histology.

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Deconvolution of cell types from bulk gene expression profiling in a nonalcoholic steatohepatitis model of mice liver reveals global alteration of macrophages and hepatic stellate cells

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