海洋真菌次生代谢产物Xyloketal B对AS抗氧化应激治疗的脂代谢组学研究

Previous studies suggested Xyloketals isolated from marine mangrove endophytic fungus were a series of novel products with unique structure. Xyloketals showed a more super and more efficient activities of anti-atherosclerosis in the Apolipoprotein E-deficient mice than simvastatin. The remarkable anti-atherosclerosis effect may serve the Xyloketals as a promising treatment of this disease. Dysregulation of lipid homeostasis plays a central role in occurrence and development of AS. The study of lipid metabolism has become critical for exploring the etiology of AS and clarifying the validation of drugs. The project selected apoE deficient mice and collected animal serum and aorta after Xyloketals intervention. An analytical method was developed to identification lipid metabolites by LC/MS-IT-TOF. PCA and PLS-DA methods were carried out to recognize the pattern of animal lipid metabolites in the control group, model group and treatment group and then select specific lipid biomarker as a target which can be used to explore the molecular mechanism correlated with lipid metabolism on the treatment of atherosclerosis using Xyloketals. This study substantiates the content of Xyloketals basic research and confirms the potential for using Xyloketals to treat AS from lipidomics aspect.

本项目前期实验发现来自海洋真菌代谢产物的Xyloketals结构新颖，对apoE缺陷小鼠具有高效的抗动脉粥样硬化（AS）作用，与辛伐他汀相比优势显著，是一个很有潜力的治疗AS新化合物。脂质平衡功能失调在AS病变发生发展中起着关键作用。脂代谢组学对探求AS病因和明确药物的治疗效果意义重大。Xyloketals有别于其他治疗药物的全新结构可能预示着全新的脂质代谢调控过程。本项目从代谢组学入手结合生物信息学手段，收集药物干预后apoE小鼠血清和主动脉，用液相色谱串联离子阱飞行时间质谱(LC/MS-IT-TOF)分离鉴定脂质代谢物，主成分分析法(PCA)和偏最小二乘法(PLS-DA)对正常组、模型组和治疗组的脂质代谢物进行模式识别，筛选出特异性脂生物标记物，作为靶点探讨Xyloketals对AS治疗中与脂质代谢相关的分子机制。该研究将为AS的疗效提供新的评价靶标，也推动海洋创新药物的研究开发。

Xyloketals 类化合物是 2001 年中山大学林永成教授研究小组（本课题组合作团队）从南海海洋真菌 Xylaria sp. (#2508)分离出来的一系列结构珍奇的缩酮类化合物，具有抗氧化应激、调节脂代谢的生物学活性，其中Xyloketal B是活性最突出的一个先导化合物。本课题组对Xyloketal B 进行了系统的药物动力学、肝药酶代谢研究、itraq进行分子作用靶标的筛选和讨论、以NAFLD体内外模型研究了xyloketal B的疗效并探讨了其可能的脂代谢调控分子机制。综合上述研究结果，推测其可能的分子机制是以AMPK为靶点，通过AMPK/SREBP通路影响甘油三脂和胆固醇合成，从而抑制脂肪酸的从头合成，但具体的分子机制尚未明确，尚需对通路中的上下游靶标（mTOR、PPAR、DJ-1等）进行系统的验证。本研究绘制出了xyloketal B可能的机制调控网络图谱，以明确Xyloketal B的脂代谢调控机制，指导后续Xyloketal类化合物的结构、剂型改造及临床给药方案，推动海洋药物研究进程。