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Understanding the cellular interactome of non-alcoholic fatty liver disease

ABSTRACT: Summary Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions, with a global prevalence of 25% in the adult population. Non-alcoholic steatohepatitis (NASH), which can lead to cirrhosis, has become the leading indication for liver transplantation in both Europe and the USA. Liver fibrosis is the consequence of sustained, iterative liver injury, and the main determinant of outcomes in NASH. The liver possesses remarkable inherent plasticity, and liver fibrosis can regress when the injurious agent is removed, thus providing opportunities to alter long-term outcomes through therapeutic interventions. Although hepatocyte injury is a key driver of NASH, multiple other cell lineages within the hepatic fibrotic niche play major roles in the perpetuation of inflammation, mesenchymal cell activation, extracellular matrix accumulation as well as fibrosis resolution. The constituents of this cellular interactome, and how the various subpopulations within the fibrotic niche interact to drive fibrogenesis is an area of active research. Important cellular components of the fibrotic niche include endothelial cells, macrophages, passaging immune cell populations and myofibroblasts. In this review, we will describe how rapidly evolving technologies such as single-cell genomics, spatial transcriptomics and single-cell ligand-receptor analyses are transforming our understanding of the cellular interactome in NAFLD/NASH, and how this new, high-resolution information is being leveraged to develop rational new therapies for patients with NASH.

SUBMITTER: Wallace S

PROVIDER: S-EPMC9284456 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background & Aims: Cirrhosis and liver cancer are potential outcomes of advanced nonalcoholic fatty liver disease (NAFLD). It is not clear what factors determine whether patients will develop advanced or mild NAFLD, limiting non-invasive diagnosis and treatment before clinical sequelae emerge. We investigated whether DNA methylation profiles can distinguish patients with mild disease from those with advanced NAFLD, and how these patterns are functionally related to hepatic gene expression. Methods: We collected frozen liver biopsies and clinical data from patients with biopsy-proven NAFLD (56 in the discovery cohort and 34 in the replication cohort). Samples were divided into groups based on histologic severity of fibrosis: F0?1 (mild) and F3?4 (advanced). DNA methylation profiles were determined and coupled with gene expression data from the same biopsies; differential methylation was validated in subsets of the discovery and replication cohorts. We then analyzed interactions between the methylome and transcriptome. Results: Clinical features did not differ between patients known to have mild or advanced fibrosis based on biopsy analysis. There were 69,247 differentially methylated CpG sites (76% hypomethylated, 24% hypermethylated) in patients with advanced vs mild NAFLD (P<.05). Methylation at FGFR2, MAT1A, and CASP1 was validated by bisulfite pyrosequencing and the findings were reproduced in the replication cohort. Methylation correlated with gene transcript levels for 7% of differentially methylated CpG sites, indicating that differential methylation contributes to differences in expression. In samples with advanced NAFLD, many tissue repair genes were hypomethylated and overexpressed, whereas genes in certain metabolic pathways, including 1-carbon metabolism, were hypermethylated and under-expressed. Conclusions: Functionally relevant differences in methylation can distinguish patients with advanced vs mild NAFLD. Altered methylation of genes that regulate processes such as steatohepatitis, fibrosis, and carcinogenesis indicate the role of DNA methylation in progression of NAFLD. Three technical replicates were included for quality control along with 35 mild NAFLD (33 unique samples) and 24 advanced NAFLD (23 unique sample). One sample per technical duplication was randomly included for a total of 56 NAFLD samples used for study.

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Understanding the cellular interactome of non-alcoholic fatty liver disease

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