NK细胞通过分泌IFN-γ和OPN诱导肝脏胰岛素抵抗

The liver is a metabolic organ that plays a key role in regulating both glucose and lipid metabolism. Hepatic insulin resistance is very important for the pathogenesis of T2DM, but it is not yet clear which factors could have impact on it. The liver is also an immune organ with a large proportion of innate immune cells, including NK cells, NKT cells and macrophages. NK cells have an important role for the innate immune response of liver, but their role and mechanism in T2DM remain unclear. Our studies have found that the expression of cytokines including IL-18, IFN-γ and OPN is upregulated in the liver of patients with T2DM, suggesting that NK cells may be in the actived state and play effects. Additionally, we found that the expression of IFN-γ and OPN were upregulated in the liver NK cells in rats with T2DM. We would like to study whether NK cells are involved in hepatic insulin resistance and how the mechanism works. We hope that the study on the effect of NK cells on insulin resistance could link the immune cells to metabolic diseases, which would expand the role of NK cells and enrich ours understanding of NK cells as well as provides potential targets for the prevention and treatment of T2DM.

肝脏是糖和脂代谢的重要器官，肝脏胰岛素抵抗对2型糖尿病（T2DM）发病非常重要，但其影响因素并不明确。肝脏又是重要的免疫器官，含有NK细胞、NKT细胞、枯否细胞等多种固有免疫细胞。NK细胞对于肝脏的固有免疫应答起重要作用，但是其在T2DM中的作用及机制仍不清楚。我们的前期研究发现，T2DM患者肝脏中与NK细胞活化、功能相关的细胞因子IL-18、IFN-γ及骨桥蛋白(Osteopontin, OPN)等表达上调，提示NK细胞可能处于活化状态并发挥效应。并且我们发现T2DM大鼠NK细胞IFN-γ及OPN表达也上调。NK细胞是否参与肝脏胰岛素抵抗又是通过何种机制发挥作用是本课题的目的所在。我们希望通过对NK细胞诱导胰岛素抵抗的研究，将免疫细胞与代谢性疾病联系起来，既可以扩展NK细胞的作用领域，丰富人们对NK细胞的认识，也为预防和治疗T2DM寻找潜在的干预靶点。

肝脏是糖和脂代谢的重要器官，也是免疫器官。NK细胞对于肝脏的免疫应答起重要作用，但是其在糖和脂代谢中的作用及机制仍不清楚。有研究表明，内质网应激可以促进肝脏胰岛素抵抗及脂质沉积。NK细胞是否可以通过影响内质网应激参与肥胖小鼠糖和脂代谢紊乱并不清楚。我们的研究发现，肥胖小鼠肝脏NK细胞的数目和比例均有所增加。清除NK细胞后，肥胖小鼠的糖耐量、肝脏脂质沉积及内质网应激有所减轻。相对于低脂喂养小鼠，肥胖小鼠肝脏NK细胞分泌更高水平的骨桥蛋白(Osteopontin, OPN)，体外实验证实OPN 可以引起肝细胞内质网应激，降低肝细胞对胰岛素的敏感性。综上，NK细胞通过分泌OPN诱导肝脏内质网应激参与肥胖小鼠的胰岛素抵抗和脂代谢紊乱。