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Hepatocytes demarcated by EphB2 contribute to the progression of non-alcoholic steatohepatitis

ABSTRACT: Current therapeutic strategies for treating non-alcoholic steatohepatitis (NASH) have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. Here, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during NASH development in mice and humans. The bifurcation of hepatocyte trajectory with NASH progression was conserved between mouse and human. At the non-alcoholic fatty liver (NAFL) stage, hepatocytes exhibited metabolic adaptation, whereas at the NASH stage, a subset of hepatocytes was enriched for the signatures of cell adhesion and migration, which was mainly demarcated by receptor tyrosine kinase EphB2. EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomously inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in NASH. Thus, EphB2 expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE189600 | GEO | 2023/02/08

REPOSITORIES: GEO

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