RIP1 kinase activity promotes steatohepatitis through mediating cell death and inflammation in macrophages

Abstract

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 key regulator of apoptosis, necroptosis and inflammation, we thus hypothesized that the kinase activity of RIP1 may be involved in the pathogenesis of NASH. Wild-type and RIP1 kinase-dead (Rip1 K45A/K45A ) mice were fed with methionine-and choline-deficient diet (MCD) or high-fat diet (HFD) to establish distinct NASH models. In both models, compared to WT mice, Rip1 K45A/K45A mice exhibited significantly less liver injury, less steatosis, decreased inflammation, and less cell death in liver tissue. Moreover, hepatic fibrosis as characterized by Sirius Red staining, expression of α-SMA and other fibrosis markers, were significantly alleviated in Rip1 K45A/K45A mice than WT controls. Furthermore, using bone marrow transplantation to create chimeric mice, we found that it is the RIP1 kinase in hematopoietic-derived macrophages contributing mostly to the disease progression in NASH.Results from in vitro studies were in agreement with the in vivo data, demonstrating that RIP1 kinase was required for inflammasome activation and cell death induced by saturated fatty acid (palmitic acid) in bone marrow-derived macrophages (BMDMs). At last, we also found that the phosphorylation and expression of RIP1 was obviously increased in patients with NAFLD or NASH, but not in healthy controls. In summary, our results indicate that RIP1 kinase is activated during the pathogenesis of steatohepatitis, and consequently induces inflammation and cell death in macrophages, contributing to the disease progression. Our study suggests that macrophage RIP1 kinase represents a specific and potential target for the treatment of NASH.

Role of Hepatocyte RIPK1 in Maintaining Liver Homeostasis during Metabolic Challenges

“…While the pathophysiological roles of RIPK1 have primarily been studied in inflammatory diseases and pathogen infections, emerging evidence suggests its involvement in metabolism-related pathways [15,16,33] . Previous studies, including our own, have linked RIPK1's kinase activity to the pathogenesis of metabolic diseases like NASH, indicating a metabolic regulatory role of RIPK1 kinase [13,14,34] . Subsequently, UDP-glucose 6dehydrogenase (UGDH) and UDP-glucuronate metabolism are found to suppress NASH pathogenesis and control hepatocyte apoptosis through inhibiting RIPK1 kinase activity, further solidifying the connection between RIPK1 kinase activity and metabolism during the pathogenesis of NASH [35] .…”

“…Both functions play crucial regulatory roles across a spectrum of physiological and pathological scenarios. Notably, the kinase activity of RIPK1 has been extensively studied due to its association with the deleterious effects in pathological situations [11][12][13][14] . In contrast, the scaffold function of RIPK1 is less studied and current evidences suggest that it plays an essential role in maintaining tissue homeostasis within physiological context [15,16] .…”