Choi Hong Y, Choi Senna, Iatan Iulia, Ruel Isabelle, Genest Jacques
Research Institute of the McGill University Health Centre, Montréal, QC H4A 3J1, Canada.
Centre for Heart Lung Innovation, Department of Medicine, St. Paul's Hospital, University of British Columbia, Vancouver, BC V6Z 1Y6, Canada.
Biomedicines. 2023 Feb 15;11(2):561. doi: 10.3390/biomedicines11020561.
ATP-binding cassette transporter A1 (ABCA1) has been identified as the molecular defect in Tangier disease. It is biochemically characterized by absence of high-density lipoprotein cholesterol (HDL-C) in the circulation, resulting in the accumulation of cholesterol in lymphoid tissues. Accumulation of cholesterol in arteries is an underlying cause of atherosclerosis, and HDL-C levels are inversely associated with the presence of atherosclerotic cardiovascular disease (ASCVD). ABCA1 increases HDL-C levels by driving the generation of new HDL particles in cells, and cellular cholesterol is removed in the process of HDL generation. Therefore, pharmacological strategies that promote the HDL biogenic process by increasing ABCA1 expression and activity have been intensively studied to reduce ASCVD. Many ABCA1-upregulating agents have been developed, and some have shown promising effects in pre-clinical studies, but no clinical trials have met success yet. ABCA1 has long been an attractive drug target, but the failed clinical trials have indicated the difficulty of therapeutic upregulation of ABCA1, as well as driving us to: improve our understanding of the ABCA1 regulatory system; to develop more specific and sophisticated strategies to upregulate ABCA1 expression; and to search for novel druggable targets in the ABCA1-dependent HDL biogenic process. In this review, we discuss the beginning, recent advances, challenges and future directions in ABCA1 research aimed at developing ABCA1-directed therapies for ASCVD.
ATP结合盒转运体A1（ABCA1）已被确定为丹吉尔病的分子缺陷。其生化特征是循环中缺乏高密度脂蛋白胆固醇（HDL-C），导致胆固醇在淋巴组织中蓄积。动脉中胆固醇的蓄积是动脉粥样硬化的根本原因，而HDL-C水平与动脉粥样硬化性心血管疾病（ASCVD）的存在呈负相关。ABCA1通过驱动细胞中新的HDL颗粒的生成来提高HDL-C水平，并且在HDL生成过程中细胞胆固醇被清除。因此，通过增加ABCA1的表达和活性来促进HDL生物合成过程的药理学策略已被深入研究以降低ASCVD。已经开发了许多上调ABCA1的药物，并且一些药物在临床前研究中显示出有前景的效果，但尚未有临床试验取得成功。长期以来，ABCA1一直是一个有吸引力的药物靶点，但临床试验的失败表明上调ABCA1进行治疗存在困难，这也促使我们：加深对ABCA1调节系统的理解；开发更具体、更精密的上调ABCA1表达的策略；并在依赖ABCA1的HDL生物合成过程中寻找新的可成药靶点。在这篇综述中，我们讨论了旨在开发针对ASCVD的ABCA1导向疗法的ABCA1研究的开端、最新进展、挑战和未来方向。
