Apoc3基于能量代谢调控CD8+T和NK细胞的活性及其分子机制

Apolipoprotein C3 (APOC3) causes hypertriglyceridemia by inhibiting the activity of lipoprotein LPL. Hypertriglyceridemia is associated with atherosclerosis, diabetes, and other diseases. The occurrence of these diseases is often accompanied by the disturbance of immune function in the body. Our previous studies showed that the frequency and activity of CD8+ T cells in the spleen of APOC3 transgenic mice were increased, while those of NK cells were significantly decreased in Apoc3 transgenic mice. The metabolisms of CD8+ T and NK cells were also altered in Apoc3 transgenic mice. Based on these previous studies, herein we aim to: (1) investigate the effect of APOC3 on the metabolism and function of CD8+ T and NK cells by using Apoc3+/+ mouse model and the flow cytometry technique; (2) further clarify the relationship among apoc3, the metabolism and function of CD8+ T and NK cells. We would like to elucidate how Apoc3 regulates the function of CD8+ T and NK cells, as well as the underlying molecular mechanisms and their relationship with inflammation or anti-tumor properties. Our study may provide the link between hyperlipidemia and immune function. Our results from the current proposal will likely provide both theoretical and experimental evidences for the future prevention and treatment of hyperlipidemia-related metabolic diseases.

载脂蛋白C3（Apoc3）通过抑制脂蛋白酶LPL活性，导致体内高甘油三酯血症。高甘油三酯血症与动脉粥样硬化、糖尿病等代谢相关性疾病有关，这些疾病的发生往往伴随着体内免疫功能的紊乱。本课题组通过引进Apoc3转基因小鼠，发现该小鼠脾脏CD8+T细胞的频率及活性上调，而NK细胞受到下调，且CD8+T和NK细胞的能量代谢方式发生变化。本项目拟在此研究基础上，利用Apoc3转基因模型，流式细胞术等技术明确Apoc3影响CD8+T细胞和NK细胞的活性及其生物学意义，探讨Apoc3基于能量代谢调控CD8+T和NK细胞活性的分子机制。本项目不仅从理论上丰富高脂血症调控机体免疫功能的认识，而且为干预高脂血症代谢相关性疾病防治提供理论和实验依据。

载脂蛋白C-III（ApoC3）通过抑制脂蛋白脂酶调节甘油三酯的代谢。本项目基于ApoC3转基因小鼠（ApoC3TG），探讨ApoC3和ApoC3诱导的高脂血症对NK细胞和CD8+T细胞代谢和活性的调节作用及其分子机制，并分析该调节作用是否参与肿瘤的进展。结果发现，ApoC3TG小鼠NK细胞的数量和功能受损，但这并不归因于ApoC3的直接作用。ApoC3诱导的高脂血症通过增加CD36介导的FFA摄取激活了NK细胞过氧化物酶体增殖物激活受体（PPAR-γ），从而驱动了NK细胞以氧化磷酸化为主的代谢重编程和活性下调。同时，ApoC3诱导的高脂血症上调DC的免疫耐受活性。脂质积聚的 DC依赖活性氧（ROS）增加PD-L1、TGF-β1和NKG2D配体的表达，并在体内抑制NK细胞活性。与NK细胞和DC不同，在ApoC3TG小鼠中观察到CD8+T细胞活性上调，并抑制肿瘤生长。代谢的变化和RNA测序分析，提示ApoC3TG小鼠CD8+T细胞的活化与周围细胞的接触有关。ApoC3TG小鼠巨噬细胞表现出活化的表型，并通过活化CD8+T细胞抑制体内肿瘤的进展。ApoC3与TLR2/TLR4交联诱导脾酪氨酸激酶（Syk）激活促进了cPLA2/NOX2/ROS介导的非经典途径炎症小体活化。另外，游离脂肪酸的氧化磷酸化增加产生的线粒体ROS促进了经典途径的炎症小体活化，这对ApoC3TG小鼠巨噬细胞的活化发挥了辅助作用。本研究揭示了ApoC3诱导的高脂血症中免疫细胞发生的动态变化，丰富了高脂血症调控机体免疫功能的认识，为干预高脂血症代谢相关性疾病和肿瘤提供理论依据。