Abstract 15537: The Role of Liver Epsins in Nonalcoholic Steatohepatitis

Abstract

Introduction: Nonalcoholic steatohepatitis (NASH) is a chronic liver disease that is associated with high risks of cardiovascular diseases. Epsin is an evolutionarily conserved protein family that is involved in clathrin-mediated endocytosis. We found that both Epsin1/2 expressions in the liver are significantly up-regulated by the Western Diet (WD) induced NASH mice model, as well as in the liver biopsy of NASH patients. Hypothesis: We hypothesize that the expressions of Epsin1 and Epsin2 in the liver are required for NASH progression. Methods: We conditionally deleted Epsin1/2 using Albumin-Cre (Liver-DKO). We then induced a mouse model of NASH by feeding both WT and Liver-DKO mice a WD for 52 weeks. We used single cell multiome, combined with molecular approaches to study the mechanisms. We tested a strategy to deliver Epsin1/2 siRNAs encapsulated nanoparticles (NPs) targeting the liver via intravenous injection to treat diet induced NASH in mice. Results: We found WD-fed Liver-DKO mice have significant reductions in hepatic fibrosis formation and less lipid accumulation, and this was associated with better glucose and insulin tolerance, as well as lower serum aspartate transaminase (AST) and alanine aminotransferase (ALT) compared with WD-fed WT mice. Through analysis of the single cell multiome from the WT and Liver-DKO livers, we found more Kupffer cell in WT NASH mice compared with DKO. Interestingly, monocyte-derived inflammantory Kupffer cell (KCs) are enriched in WD-fed WT mice, however, embryonic-derived KCs are the enriched in liver DKO, and associate with dramatically reduced total KCs population. We also found that HNF4a was dramatically reduced in WD-fed WT mice, but its expression was preserved in WD-fed Liver-DKO mice, suggesting the loss of hepatocyte identity was inhibited by Epsins deletion. Therapeutically, we found significant resolution of hepatic fibrosis after knockdown of Epsin1/2 siRNA NP treatment. Conclusions: Liver specific deletion of Epsin1/2 significantly inhibits NASH progression by suppression of inflammation that protects hepatocytes from severe chronic injury. Our preclinical data suggests specially targeting Epsin1 and Epsin2 in the liver could be a promising therapeutic strategy for NASH treatment.