果胶五糖解除胆汁酸对CYP7A1转录的反馈抑制降低胆固醇的分子机制研究

Bile acid in the liver can cause the feedback inhibition of Cholesterol 7α-hydroxylase (CYP7A1) transcription that is the key gene of enzyme for bile acid biosynthesis. In previous studies we found that haw pectin pentasaccharide (HPPS) could significantly upregulate CYP7A1 transcription in the liver and promote the conversion of cholesterol to bile acids, thereby reducing cholesterol level. However, the mechanism is not clear. Studies had shown that bile acids were the natural ligands of nuclear receptors that regulated CYP7A1 at the level of gene transcription. This project will analyze how HPPS consumption to affect the bile acids concentration in enterohepatic circulation and the expression of bile acids reabsorption- and transportation-related protein in the lleum and nuclear receptors regulating CYP7A1 transcription in hamsters. On the above basis, it will reveal the molecular mechanism of HPPS to relieve the feedback inhibition of CYP7A1 transcription by bile acid and ascertain the molecular pathway of HPPS to regulate and promote CYP7A1 transcription by nuclear receptors. This project will provide the new ideas in developing food materials to prevent and cure hypercholesterolemia and metabolic diseases caused by metabolic disorders.

肝脏中的胆汁酸对其自身合成关键酶胆固醇7α-羟化酶基因（CYP7A1）的转录具有反馈抑制作用。然而，前期研究中我们发现山楂果胶五糖（HPPS）能够显著提高肝脏中CYP7A1的转录，促进胆固醇向胆汁酸的转化，从而降低肝脏及血清中胆固醇水平，其机制不明。文献报道，胆汁酸是CYP7A1转录调控相关核受体的天然配体，胆汁酸与其结合后可通过一定的路径调控CYP7A1的转录。本项目通过动物实验，分析HPPS喂养对仓鼠肝肠循环中胆汁酸浓度变化、胆汁酸在回肠中的重吸收和转运相关蛋白的表达以及CYP7A1转录调控相关核受体表达的影响，揭示HPPS解除胆汁酸对CYP7A1转录的反馈抑制降低胆固醇的分子机制，确定HPPS通过核受体调控并促进CYP7A1转录的分子路径。本项目为高胆固醇血症及其代谢紊乱所引起的代谢类疾病的预防与治疗食品素材的开发提供了新的思路。

研究表明，血液中胆固醇含量过高是导致高血压、动脉硬化、冠心病等众多心脑血管疾病的主要因素。目前，还没有很好的方法治愈这类疾病。因此，阻止这类疾病的发生显得尤为重要。山楂是我国北方地区重要的栽培水果，资源十分丰富，但是长久以来其深加工利用率非常低。本项目以山楂果胶诱导而来的酸性山楂果胶五糖为主要原料，以小鼠为模型动物，研究了其对小鼠肝肠循环和粪便中胆汁酸浓度变化、胆汁酸在回肠中的重吸收和转运相关蛋白的表达以及对CYP7A1转录调控相关核受体表达的影响。结果表明，山楂果胶五糖可以显著降低肝脏和回肠中胆汁酸的含量，减小肝肠循环中总胆汁酸池的容量，促进胆汁酸在粪便中的排放。分子机理的研究表明，山楂果胶五糖诱导了肝肠循环中胆汁酸转运相关蛋白的表达，尤其是BSEP，达到显著水平；钝化了胆汁酸合成调控核受体FXR/SHP以及FXR/FGF15/FGFR4，但是促进了LXRα表达。最终，显著增加了胆汁酸合成基因CYP7A1的表达。本项目结果揭示了山楂果胶五糖解除胆汁酸对CYP7A1转录反馈抑制的分子机理，确定了其通过核受体调控并促进CYP7A1转录的分子路径，为高胆固醇血症及其代谢紊乱所引起的代谢类疾病的预防与治疗食品素材的开发提供了新的思路。