Litvinov Dmitry Y, Savushkin Eugeny V, Dergunov Alexander D
National Research Centre for Preventive Medicine, 10, Petroverigsky Street, 101990, Moscow, Russia.
Pharmaceut Med. 2019 Dec;33(6):465-498. doi: 10.1007/s40290-019-00308-w.
Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing 'biological oxidations' activate cholesterol efflux and the substances influencing 'Signaling by GPCR and PTK6' inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.
胆固醇流出是保护血管系统免受动脉粥样硬化病变发展影响的关键过程。各种细胞外和细胞内事件会影响细胞流出过量胆固醇的能力。为了探索促进或抑制胆固醇流出的可能途径和过程，我们应用了化学信息学和生物信息学相结合的方法。我们对已发表的关于影响胆固醇流出的各种物质的数据进行了全面分析，发现了153种低分子量物质，它们被纳入了生物活性化学实体（ChEBI）数据库。对在Reactome数据库中识别出的物质进行了通路富集分析，并在93条重要通路中选择了45种物质。最常见的通路包括与细胞内胆固醇主动转运相关的能量依赖过程、脂蛋白代谢和脂质转运以及信号通路。胆固醇流出的激活剂和抑制剂在不同通路中的分布并不均匀：影响“生物氧化”的物质激活胆固醇流出，而影响“GPCR和PTK6信号传导”的物质抑制流出。该分析可用于寻找和设计针对结构和功能性高密度脂蛋白缺乏症治疗的流出效应器。
