1568-P: Identification of Stage-Specific Hepatocytes That Contribute to Nonalcoholic Steatohepatitis Progression Free

Current therapeutic strategies for treating an advanced form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), have failed to alleviate liver fibrosis, which is a devastating feature leading to hepatic dysfunction. To identify potential novel therapeutic targets, we integrated single-nucleus transcriptomics and epigenomics to characterize all major liver cell types during the progression from nonalcoholic fatty liver (NAFL) to NASH in mice and humans. We found that the hepatocyte trajectory switched from metabolic adaptation to cell adhesion and migration when the NAFLD stage transited from NAFL to NASH. The trajectory switch was conserved between mouse and human. The hepatocyte trajectory leading to NASH was enriched for a receptor tyrosine kinase, EphB2. The transcription of EphB2 in hepatocytes was activated by Notch signaling pathway and sufficient to induce cell-autonomous inflammatory response in mouse and human induced pluripotent stem cell (hiPSC) derived-hepatocytes. EphB2 loss-of-function specifically in hepatocytes ameliorated inflammation and fibrosis in mouse models of NASH. Thus, NASH-stage specific hepatocytes were demarcated by EphB2 and may serve as a potential therapeutic target.