Hepatocyte cell death and liver
inflammation have been well recognized as central characteristics of
nonalcoholic steatohepatitis (NASH), however, the underlying molecular basis remains elusive. The
kinase receptor-interacting
protein 1 (RIP1) is a multitasking molecule with distinct functions in regulating apoptosis, necroptosis, and
inflammation. Dissecting the role of RIP1 distinct functions in different pathophysiology has absorbed huge research enthusiasm. Wild-type and RIP1
kinase-dead (Rip1K45A/K45A) mice were fed with high-fat diet (HFD) to investigate the role of RIP1
kinase activity in the pathogenesis of NASH. Rip1K45A/K45A mice exhibited significantly alleviated NASH phenotype of hepatic
steatosis, liver damage,
fibrosis as well as reduced hepatic cell death and
inflammation compared to WT mice. Our results also indicated that both in vivo lipotoxicity and in vitro
saturated fatty acids (
palmitic acid) treatment were able to induce the
kinase activation of RIP1 in liver macrophages. RIP1
kinase was required for mediating
inflammasome activation, apoptotic and necrotic cell death induced by
palmitic acid in both bone marrow-derived macrophage and mouse primary Kupffer cells. Results from chimeric mice established through lethal irradiation and
bone marrow transplantation further confirmed that the RIP1
kinase in hematopoietic-derived macrophages contributed mostly to the
disease progression in NASH. Consistent with murine models, we also found that RIP1
kinase was markedly activated in human NASH, and the
kinase activation mainly occurred in liver macrophages as indicated by immunofluorescence double staining. In summary, our study indicated that RIP1
kinase was phosphorylated and activated mainly in liver macrophages in both experimental and clinical NASH. We provided direct genetic evidence that the
kinase activity of RIP1 especially in hematopoietic-derived macrophages contributes to the pathogenesis of NASH, through mediating
inflammasome activation and cell death induction. Macrophage RIP1
kinase represents a specific and potential therapeutic target for NASH.