Abstract 512: Mechanisms And Therapeutic Targeting Of Epsins In Regulating Liver Steatosis

Abstract

Background: Chronic liver disease, such as non-alcoholic fatty liver disease (NAFLD), is one of the most prevalent diseases, with 4.5 million people diagnosed in the U.S. in 2018. If untreated, fibrosis-induced cirrhosis will eventually develop into hepatocellular carcinoma. Epsins are highly conserved endocytic adaptor proteins, participating in selected membrane receptor endocytosis. Globally disruption of both epsin 1 and 2 induced embryonic lethality by disruption of Notch signaling pathway, which has recently been recognized as a key player in metabolism. Thus, we aimed to study the role of epsins in controlling lipid metabolism and genes involved in live immunity. Hypothesis: We hypothesize that epsins promote the development of liver diseases, including NAFLD, particularly non-alcoholic steatohepatitis (NASH). Methodology and Results: Bulk RNA-seq analysis indicated that most differentially expressed genes (DEGs) enriched in lipid metabolism were down-regulated and immune function up-regulated in epsins liver DKO. RT-PCR confirmed other DEGs such as Il1b and Ccr5 expression. Compared to WT mice, epsins liver DKO mice harbor more Kupffer cells, residential macrophages in the liver that are thought to play a role in fighting infection and harmful insults. Consistent with this, further mining bulk RNA-seq data revealed that Kupffer cells/macrophages markers, including F4/80 and Cd11b, were increased in liver DKO. Moreover, the master transcription factor, Spi1 (PU.1), increased in liver DKO. Furthermore, RT-qPCR showed the upregulation of F4/80, Cd11b, and Spi1 in liver from WT and epsins DKO mice. Importantly, liver samples from epsin liver DKO mice contain more F4/80-positive cells. Single-cell RNA sequencing data suggested elevated Kupffer cells in Liver DKO mice. As Kupffer cells play a significant anti-inflammatory role and epsins depletion reduces lipid synthesis, we anticipate that epsins deficiency in liver will combat liver inflammation and damage caused by a build-up of fat in the liver leading to NASH. Conclusion: Epsins in liver promote lipid synthesis and suppress immune function by reducing Kupffer cell development. Targeting epsins may provide a new strategy to treat chronic liver diseases, such as cirrhosis and NASH.