结合影像质谱技术、代谢及脂质组学研究阐明黄芩调控胆固醇代谢转化机理

Cardiovascular diseases had been one of the main causes of death all over the world which is mainly due to hypercholesterolemia. Lipid metabolism disorder is the major cause of hypercholesterolemia and the most effective way to regulate lipid metabolism disorder is to inhibit the production of cholesterol. Statins are the drugs that are commonly used to treat hypercholesterolemia. The working principle is to suppress the HMG-CoA reductase in liver which could inhibit the formation of mevalonic acid, the intermediate of cholesterol. However, patients might suffer adverse side effects including muscle pain, weakness and memory loss. ..The medicinal value of Chinese medicine is well recognized and currently Chinese medicine is served as an alternative method for disease treatment. Our preliminary studies showed that the water extract of Radix Scutellariae could lower the total cholesterol and LDL-C level. It was anticipated that Radix Scutellariae could regulate the lipid metabolism pathway which may be valuable for curing lipid metabolism disorder. Based on previous research, we aim to apply the MALDI imaging technique to investigate the distribution of metabolites on various tissues so as to understanding the mechanism of lipid metabolism regulation. In addition, metabolomics and lipidomics studies will be done to reveal the targeted metabolites, related pathways and the mechanisms on how Radix Scutellariae could regulate the cholesteol metabolisms, and hence to provide scientific evidence for the development of hypocholesteolemic drug using Radix Scutellariae’s active compounds.

心血管疾病为现时世界各地主要的杀手之一，其主要成因为高胆固醇血症所引起，当中与脂质代谢紊乱有莫大的关系。目前主要治疗高脂血症的西方药物为他汀类药物，其机理主要是抑制肝细胞的HMG-CoA 还原酶，减少胆固胆中间体甲羟戊酸的生成。但他汀类药物副作用大，长期高剂量服用可能出现不良反应如肌痛、乏力、呼吸困难、记忆力减退等。然而不少中药被发现具有药用疗效, 而且疗效较持久和不良反应较少，令中药治疗被视为理想的替代疗法。我们前期研究发现，黄芩水提取物具降血脂及胆固醇作用，可改善大鼠血浆总胆固醇和LDL-C。本课题拟在以往的研究基础上，应用影像质谱技术探究小分子及脂质代谢物于生物组织上的分布情形，藉此了解黄芩降血脂及胆固醇的作用机理。另外，本课题拟利用代谢脂与组学手段，了解黄芩如何调控胆固醇代谢，阐明黄芩提取物的作用靶标、相关通路和作用机理。为研发黄芩有效成份作为调控胆固醇药物提供理论依据。

高胆固醇血症与脂质代谢紊乱有莫大的关系。因此，了解胆固醇代谢机理对研究调控胆固醇有莫大幫助。本项目首次结合影像质谱、脂质组学及代谢组学阐明黄芩调控胆固醇代谢转化的机理。通过建立高脂饮食诱导的高脂血症模型，發現黄芩水提取物可以改善高脂饮食所带来的影响。例如:黄芩水提取物能通过降低脂质合成(ACC、FAS、HMGCR, LDLR)和增加脂质分解代谢(PPARα、LC3)蛋白的表达来起到降低血脂的作用; 在脂质及代谢组学分析中找出黄芩提取物调节五十余个内源性标记物，當中涉及氨基酸代谢，胆固醇代谢，胆汁酸代谢，脂肪酸代谢，脂质代谢。此外, 脂质代谢物分子影像顯出代谢物磷脂醯胆碱类(PC(16:0/18:1))、半乳糖醯基鞘氨醇(3-O-sulfogalactosylceramide)、磷脂丝胺酸类(PS(22:5/15:0))、甘油磷脂酸类(PA(22:4/22:5))對调节糖类，蛋白质，及脂肪代谢有关。这些研究成果为脂质代谢机理提供了新思路，对进一步研究调控胆固醇有突破性的发展。