膳食纤维肠道代谢产物调节巨噬细胞胆固醇外流及其抗动脉粥样硬化作用研究

Dietary fiber plays an important role in the prevention of metabolic diseases, but its potential effect on atherosclerosis (AS) and the underlying mechanism are still unclear. Since macrophage foam cell formation is a critical step in the early stage of AS, we focus our research on the effects of short-chain fatty acids, the microbiota metabolites from dietary fiber, on AS and its underlying mechanism. Our strategies are as follows: Firstly, a cross-sectional and prospective study will be carried out in subjects with diagnosed coronary heart diseases (CHD) and healthy controls to examine the correlation between dietary fiber intake and plasma short-chain fatty acid levels and risk factors for the progression and prognosis of AS. Secondly, studies in an AS mouse model with antibiotics to suppress intestinal flora will be carried out to further clarify the effects of dietary fiber and short-chain fatty acids on macrophage cholesterol efflux and atherosclerotic plaque formation. Thirdly, macrophage cell line will be applied to extensively explore the potential mechanism by which the interaction of short-chain fatty acids and G protein-coupled receptor GPR41/GPR43 mediates macrophage cholesterol efflux. This study will uncover the protective effect of dietary fiber on AS prevention from the prespective of nutritional metabolism and extend the strategies in AS prevention through nutritional and metabolic intervention.

膳食纤维在预防代谢性疾病中具有重要作用，然而其对动脉粥样硬化（AS）防治效应及其机制缺乏深入研究。我们以巨噬细胞胆固醇外流为切入点，围绕巨噬泡沫细胞形成这一AS早期核心病理变化探讨膳食纤维肠道代谢产物短链脂肪酸对AS的影响及其分子机制。首先利用冠心病人群及健康对照人群，通过横断面和前瞻性队列研究，首次深入探讨中国人群中膳食纤维摄入及其肠道代谢产物短链脂肪酸水平与AS危险因素、进展及预后的关联。然后在ApoE基因敲除（ApoE-/-）小鼠AS模型中，利用抗生素抑制肠道菌群进一步明确膳食纤维及其肠道代谢产物对小鼠巨噬细胞胆固醇外流和AS斑块形成的影响。在此基础上，采用巨噬细胞模型在体外深入探讨短链脂肪酸激活G蛋白偶联受体GPR41/GPR43对巨噬细胞胆固醇外流的调控机制。本研究将从营养代谢新角度阐明膳食纤维预防AS效应及其分子机理，为建立适合我国人群的AS早期营养干预措施提供科学依据。

膳食纤维在预防代谢性疾病中具有重要作用，然而其对动脉粥样硬化防治效应及其机制缺乏深入研究。短链脂肪酸（SCFAs），膳食纤维肠道菌群发酵终产物，已被证明在调节宿主的营养、代谢和免疫方面发挥重要作用。然而短链脂肪酸是否会影响小肠的胆固醇吸收进而影响动脉粥样硬化疾病具体机制还不清楚。本课题探讨可溶性膳食纤维肠道菌群代谢产物对高胆固醇血症诱导的apoE-/-小鼠改善动脉粥样硬化的作用。探讨可溶性膳食纤维肠道菌群代谢产物对小鼠小肠结构、形态及其胆固醇吸收功能的影响作用。以人小肠上皮细胞（Caco-2）为细胞模型来探讨可溶性膳食纤维肠道菌群代谢产物对肠道胆固醇吸收功能的影响及其可能的分子机制。研究结果发现膳食纤维肠道菌群代谢产物中的短链脂肪酸丁酸可以改善apoE-/-小鼠肠道形态及功能，通过调控LXRE 抑制NPC1L1 的表达，从而减少肠道细胞胆固醇吸收；以及上调ABCG5/G8 异源二聚体的表达，使细胞内过载的胆固醇向肠腔内转运，即丁酸调控小肠胆固醇的吸收和外排作用，从而抑制小鼠体内脂质的异常蓄积，减少apoE-/-小鼠动脉粥样硬化形成过程中主动脉及主动脉窦斑块的面积，继而延缓动脉粥样硬化的发生发展。发表SCI学术论文1篇，培养研究生3名，国内外学术交流2次。