Hepatocytes demarcated by EphB2 contribute to the progression of nonalcoholic steatohepatitis. Sci Transl Med 2023 Feb 08;15(682):eadc9653
Date
02/09/2023Pubmed ID
36753562Pubmed Central ID
PMC10234568DOI
10.1126/scitranslmed.adc9653Scopus ID
2-s2.0-85147723227 (requires institutional sign-in at Scopus site) 56 CitationsAbstract
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.
Author List
Xiao Y, Batmanov K, Hu W, Zhu K, Tom AY, Guan D, Jiang C, Cheng L, McCright SJ, Yang EC, Lanza MR, Liu Y, Hill DA, Lazar MAAuthor
Yang Xiao Assistant Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsHepatocytes
Humans
Inflammation
Liver
Liver Cirrhosis
Mice
Mice, Inbred C57BL
Non-alcoholic Fatty Liver Disease
