基于“土侮木”探讨高脂血症脾虚痰浊猪肝脏TG代谢中microRNA122a-SREBP-1c-Apo A5-LPL的分子调控机制

With the increasing incidence of coronary heart disease, obesity and diabetes, high triglyceridemia (HTG) in lipid metabolism has been paid more and more attention. The main type of lipid metabolism disorder in China is HTG, the incidence of which is 4 times higher than that of hypercholesterolemia. HTG has been proved to be an independent risk factor in the pathogenesis of atherosclerosis (AS) caused by abnormal lipid metabolism. "Overstrain"and"improper diet" lead to dysfunction of the spleen to transport, and then endogenous phlegm turbidity generated.If the spleen is too hyperactive, the liver not only can overact the spleen, but is insulted by the spleen,namely the spleen insults the liver. This topic will be guided by the theory of the five elements to Chinese medicine about“Spleen insulting liver”,mini-pig models of hyperlipidemia spleen deficiency and phlegm syndrome was established by the methods of running combined high-fat and single cage feeding. And through the Chinese medicine herb intervention, which invigorates the spleen to eliminate phlegm, to observe the changes of serum TG quality in mini-pigs, will discuss the changes of the metabolism of triglyceride. From TG to microRNA122a-SREBP-1c-Apo A5-LPL the adjustment and the control of signaling pathway, elucidate the disorder of the metabolism of triglyceride in liver, and clarify the curative effect mechanism of spleen and eliminating phlegm method, reveals the scientific connotation of “Spleen insulting liver”, to enrich the theory of the five elements of TCM and to provide experimental basis for further research on the mechanism of TG-induced AS.

随着冠心病、肥胖、糖尿病发病率不断提高，脂代谢中的高甘油三酯血症（HTG）越来越受到重视，我国的脂代谢紊乱主要类型就是HTG，发病率是高胆固醇血症的4倍，在脂质代谢异常引发动脉粥样硬化（AS）的发病机制中，HTG已经被证实为独立的危险因素。“劳倦太过”、“过食肥甘”导致脾虚失健，进而痰浊内生。脾土气过于亢盛，其所不胜一行的肝木不仅不能克土，反而被土欺侮，出现“土反侮木”逆向克制现象。本课题将以中医五行学说“土侮木”理论为指导，通过跑步训练结合高脂单笼喂饲建立高脂血症脾虚痰浊证巴马小猪模型，并给予健脾祛痰中药干预，观察小猪血清TG浓度的改变，从肝脏miRNA122a-SREBP-1c-ApoA5-LPL通路的调控，阐明高脂血症脾虚痰浊证肝脏TG异常的代谢机制，并阐明健脾祛痰法的疗效机制，揭示“土侮木”的科学内涵，丰富中医脾脏象理论及五行相侮理论，也为进一步研究TG致AS的机制提供实验依据。

近 30 年来，中国人群的血脂水平逐步升高，高脂血症患病率明显增加。2012 年全国调查结果显示，成人血清总胆固醇（total cholesterol, TC）平均为 4.50 mmol/L，高胆固醇血症的患病率 4.9%；甘油三酯（triglyceride，TG）平均为 1.38 mmol/L，高 TG 血症的患病率 13.1%；高密度脂蛋白胆固醇（high-densitylipoprotein cholesterol，HDL-C）平均为 1.19 mmol/L，低 HDL-C血症的患病率 33.9%。中国成人高脂血症总体患病率高达 40.40%，较 2002 年呈大幅度上升。中医学历代经典中虽无与高脂血症相对应的病名,但现代中医学者均认同高脂血症属于中医“痰浊”范畴。而痰浊的形成又与脾虚失运密切相关,因此,以脾失健运探讨高脂血症发病机制逐渐成为热门。本课题通过跑步训练结合高脂单笼喂饲建立高脂血症脾虚痰浊证巴马小型猪模型、高脂喂饲建立高脂血症Apo E小鼠模型，并给予健脾祛痰中药干预，观察小猪及Apo E小鼠血清TG浓度的改变，从肝脏miRNA122a-SREBP-1c-ApoA5-LPL通路的调控，阐明高脂血症脾虚痰浊证TG异常的代谢机制，并阐明健脾祛痰中药的疗效机制，同时发现高脂血症脾虚痰浊猪血清高密度脂蛋白向失功能性高密度脂蛋白转变，冠脉内皮功能发生了一定程度的障碍。高脂血症Apo E小鼠肝脏脂肪变性，细胞变大，脂质沉积明显，模型组、中药组、西药组小鼠肝脏内LPL的蛋白表达水平显著降低（P<0.05）；模型组小鼠肝脏内SREBP-1C、LPL的mRNA表达有所上调。与模型组比较，中药组肝脏内SREBP-1c、APOA5、LPL的蛋白表达水平均有所降低，中药组肝脏内SREBP-1C、APOA5、LPL的基因表达水平均有所上调；肝脏脂肪变性减轻，脂质沉积不同程度降低。进而揭示“土侮木”的科学内涵，丰富中医脾脏象理论及五行相侮理论，也为进一步研究TG致AS的机制提供实验依据。