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 (Rip1^K45A/K45A) mice were fed with high-fat diet (HFD) to investigate the role of RIP1 kinase activity in the pathogenesis of NASH. Rip1^K45A/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.

肝细胞死亡和肝脏炎症已被公认为非酒精性脂肪性肝炎 (NASH) 的核心特征，然而，潜在的分子基础仍然难以捉摸。激酶受体相互作用蛋白 1 (RIP1) 是一种多任务分子，在调节细胞凋亡、坏死性凋亡和炎症方面具有不同的功能。剖析 RIP1 不同功能在不同病理生理学中的作用吸引了巨大的研究热情。用高脂饮食 (HFD) 喂养野生型和 RIP1 激酶死亡 ( Rip1 ^{K45A/K45A ) 小鼠，以研究 RIP1 激酶活性在 NASH 发病机制中的作用。}Rip1 ^K45A/K45A与WT小鼠相比，小鼠表现出肝脂肪变性、肝损伤、纤维化的NASH表型显着减轻以及肝细胞死亡和炎症减少。我们的结果还表明，体内脂毒性和体外饱和脂肪酸（棕榈酸）处理都能够诱导肝巨噬细胞中 RIP1 的激酶活化。RIP1 激酶是介导骨髓来源的巨噬细胞和小鼠原代枯否细胞中棕榈酸诱导的炎症小体活化、凋亡和坏死细胞死亡所必需的。通过致死辐射和骨髓移植建立的嵌合小鼠的结果进一步证实，造血源巨噬细胞中的 RIP1 激酶对 NASH 的疾病进展做出了主要贡献。与小鼠模型一致，我们还发现RIP1激酶在人NASH中被显着激活，免疫荧光双染表明激酶激活主要发生在肝巨噬细胞中。总之，我们的研究表明，在实验性和临床 NASH 中，RIP1 激酶主要在肝巨噬细胞中被磷酸化和激活。我们提供了直接的遗传证据，证明 RIP1 的激酶活性，尤其是在造血源性巨噬细胞中，通过介导炎性体激活和细胞死亡诱导，有助于 NASH 的发病机制。巨噬细胞 RIP1 激酶代表了 NASH 的特异性和潜在治疗靶点。我们的研究表明，在实验和临床 NASH 中，RIP1 激酶主要在肝巨噬细胞中被磷酸化和激活。我们提供了直接的遗传证据，证明 RIP1 的激酶活性，尤其是在造血源性巨噬细胞中，通过介导炎性体激活和细胞死亡诱导，有助于 NASH 的发病机制。巨噬细胞 RIP1 激酶代表了 NASH 的特异性和潜在治疗靶点。我们的研究表明，在实验和临床 NASH 中，RIP1 激酶主要在肝巨噬细胞中被磷酸化和激活。我们提供了直接的遗传证据，证明 RIP1 的激酶活性，尤其是造血源巨噬细胞中的激酶活性，通过介导炎性体激活和细胞死亡诱导，促进了 NASH 的发病机制。巨噬细胞 RIP1 激酶代表了 NASH 的特异性和潜在治疗靶点。