Nonalcoholic fatty liver disease (
NAFLD) is one of the most prevalent forms of chronic
liver disease in the United States and worldwide.
Nonalcoholic steatohepatitis (NASH), the most advanced form of
NAFLD, is characterized by hepatic steatosis associated with
inflammation and hepatocyte death. No treatments are currently available for NASH other than lifestyle changes, and the disease lacks specific
biomarkers. The
signaling lymphocytic activation molecule family 1 (
SLAMF1) protein is a self-
ligand receptor that plays a role in orchestrating an immune response to some pathogens and
cancers. We found that livers from humans and mice with NASH showed a more prominent immunohistochemistry staining for SLAMF1 than non-NASH controls. Furthermore, SLAMF1 levels are significantly increased in NASH plasma samples from mice and humans compared with their respective controls. In mice, the levels of SLAMF1 correlated significantly with the severity of the NASH phenotype. To test whether SLAMF 1 is expressed by hepatocytes, HepG2 cells and primary murine hepatocytes were treated with
palmitic acid (PA) to induce a state of lipotoxicity mimicking NASH. We found that PA treatments of HepG2 cells and primary hepatocytes lead to significant increases in SLAMF1 levels. The downregulation of SLAMF1 in HepG2 cells improved the cell viability and reduced cytotoxicity. The in vivo data using mouse and human NASH samples suggests a potential role for this
protein as a noninvasive
biomarker for NASH. The in vitro data suggest a role for SLAMF1 as a potential therapeutic target to prevent hepatocyte death in response to lipotoxicity.NEW & NOTEWORTHY This study identified for the first time SLAMF1 as a mediator of hepatocyte death in
nonalcoholic fatty liver disease (NASH) and as a marker of NASH in humans. There are no pharmacological treatments available for NASH, and diagnostic tools are limited to invasive liver biopsies. Therefore, since SLAMF1 levels correlate with
disease progression and SLAMF1 mediates cytotoxic effects, this
protein can be used as a therapeutic target and a clinical
biomarker of NASH.