SLAMF1 Mediates Hepatocyte Death in a Model of Non‐Alcoholic Steatohepatitis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common forms of chronic liver disease. NAFLD's initial phase involves hepatic stea­tosis (triglyceride accumulation in hepatocytes). NAFLD can rapidly progress to non-alcoholic steatohepatitis (NASH). NASH is characterized by increased oxidative stress, lipid peroxidation, inflammation, mitochondria dysfunction, and hepatocyte death and fibrosis. If untreated, NASH leads to cirrhosis, and in some cases, hepatocellular carcinoma. Besides lifestyle modifications (e.g., diet and exercise), we still do not have effective treatment for NASH today. Therefore, it is critical to understand the mechanisms responsible for NAFLD progression to NASH to develop efficient therapies and find disease progression biomarkers. Signaling lymphocytic activation molecule 1 (SLAMF1) protein is a self-ligand receptor involved in regulating the immune response to viruses and cancer. In the present project, we found that hepatocytes from NASH liver samples from humans and mice express high levels of SLAMF1. To confirm these findings, we used palmitic acid-treated HepG2 hepatocytes as an “in vitro” model of NASH. We found that palmitic acid treatment of HepG2 hepatocytes leads to significant increases in SLAMF1 mRNA and protein levels, which correlated with an increased hepatocyte death in response to palmitic acid treatment. To investigate the potential role of SLAMF1 in mediating the toxic effects of palmitic acid treatment, we partially blocked SLAMF1 with siRNA. Our results showed that downregulation of SLAMF1 levels in hepatocytes significantly improved cell viability and reduced the expression of the cytotoxicity and proapoptotic markers such as cleaved caspase 3 and vimentin V by hepatocytes. We also found that palmitic acid-treated hepatocytes secrete SLAMF1 in the culture medium. Our data suggest that SLAMF1, both membrane-bound and soluble form, are upregulated by palmitic acid treatment and may mediate its cytotoxic effects. SLAMF1 could be used as a potential therapeutic or diagnostic target (soluble form) for NASH.