Publication Date
2-8-2023
Journal
Science Translational Medicine
DOI
10.1126/scitranslmed.adc9653
PMID
36753562
PMCID
PMC10234568
PubMedCentral® Posted Date
8-8-2023
PubMedCentral® Full Text Version
Author MSS
Published Open-Access
yes
Keywords
Humans, Animals, Mice, Non-alcoholic Fatty Liver Disease, Liver, Hepatocytes, Liver Cirrhosis, Inflammation, Mice, Inbred C57BL
Abstract
Current therapeutic strategies for treating nonalcoholic 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 mice and humans. At the nonalcoholic 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 were mainly demarcated by receptor tyrosine kinase ephrin type B receptor 2 (EphB2). EphB2, acting as a downstream effector of Notch signaling in hepatocytes, was sufficient to induce cell-autonomous inflammation. Knockdown of Ephb2 in hepatocytes ameliorated inflammation and fibrosis in a mouse model of NASH. Thus, EphB2-expressing hepatocytes contribute to NASH progression and may serve as a potential therapeutic target.
Included in
Digestive System Diseases Commons, Endocrine System Diseases Commons, Endocrinology, Diabetes, and Metabolism Commons, Hepatology Commons, Medical Sciences Commons
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