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- Title
Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis.
- Authors
Xiao, Yang; Batmanov, Kirill; Hu, Wenxiang; Zhu, Kun; Tom, Alexander Y.; Guan, Dongyin; Jiang, Chunjie; Cheng, Lan; McCright, Sam J.; Yang, Eric C.; Lanza, Matthew R.; Liu, Yifan; Hill, David A.; Lazar, Mitchell A.
- 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. An ephrin receptor target in NASH: A subset of patients with nonalcoholic fatty liver (NAFL) progress to nonalcoholic steatohepatitis (NASH) with its associated liver inflammation and fibrosis. Xiao et al. performed single-nucleus RNA sequencing and chromatin accessibility profiling of all major mouse and human liver cell types during the transition from NAFL to NASH. They detected a subpopulation of hepatocytes that appeared during NASH development in both species, demarcated by expression of the receptor tyrosine kinase Ephb2 and cell-autonomous inflammation. Depleting Ephb2 improved inflammation and fibrosis in a mouse model of NASH. This study suggests a potential strategy to target NASH and advances our single-cell knowledge of liver disease. —CAC
- Subjects
NON-alcoholic fatty liver disease; FATTY liver; HEPATIC fibrosis; HEPATITIS; PROTEIN-tyrosine kinases
- Publication
Science Translational Medicine, 2023, Vol 15, Issue 682, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adc9653