Amyloid precursor protein promotes MASH progression by upregulating death receptor 6-mediated hepatocyte apoptosis

Metabolic dysfunction-associated steatohepatitis (MASH) is a complicated process that contributes to end-stage liver disease and, eventually, hepatocellular carcinoma. Hepatocyte apoptosis, a well-defined form of cell death in MASH, is considered the primary cause of liver inflammation and fibrosis. However, the mechanisms underlying the regulation of hepatocyte apoptosis in MASH remain largely unclear. We explored the proapoptotic effect of hepatocyte amyloid precursor protein (APP) in MASH. C57BL/6J mice were fed a Western diet plus sugar water, a high-fat high-fructose diet, or a methionine and choline deficiency diet to induce MASH. APP expression was analyzed in murine MASH specimens. App^-/- mice and mice with adeno-associated virus-mediated APP overexpression were established to study the role of APP in MASH. Palmitic acid was used to mimic lipotoxicity-induced MASH in AML12 cells. We identified a dramatic increase in APP expression in hepatocytes of patients with MASH and three different mouse models. Suppression of APP attenuated hepatic steatosis, inflammation, and fibrosis in MASH mice, whereas its restoration activated MASH pathogenesis. Furthermore, increased death receptor 6 (DR6) was observed in MASH mouse livers. Mechanistically, APP interacted with DR6, a tumor necrosis factor receptor, to facilitate DR6 expression and activation. Activated DR6 increased apoptosis in hepatocytes, which was associated with an increase in proapoptotic effectors (cleaved-caspase 3/7). Our results highlight the role of the APP-DR6 axis in hepatocyte apoptosis, inflammation activation, and fibrosis formation in murine MASH model, providing new insights into therapeutic strategies for MASH.