Choi Hong Y, Ruel Isabelle, Choi Shiwon, Genest Jacques
Cardiovascular Research Laboratories, Research Institute of the McGill University Health Center, Montreal, QC, Canada.
Front Cardiovasc Med. 2021 Dec 23;8:795868. doi: 10.3389/fcvm.2021.795868. eCollection 2021.
The capacity of macrophages to dispose of cholesterol deposited in the atherosclerotic plaque depends on their ability to activate cholesterol efflux pathways. To develop athero-protective therapies aimed at promoting macrophage cholesterol efflux, cholesterol metabolism in THP-1 monocyte-derived macrophages has been extensively studied, but the intrinsic sensitivity of monocytes and the lack of a standardized procedure to differentiate THP-1 monocytes into macrophages have made it difficult to utilize THP-1 macrophages in the same or similar degree of differentiation across studies. The variability has resulted in lack of understanding of how the differentiation affects cholesterol metabolism, and here we review and investigate the effects of THP-1 differentiation on cholesterol efflux. The degree of THP-1 differentiation was inversely associated with ATP binding cassette A1 (ABCA1) transporter-mediated cholesterol efflux. The differentiation-associated decrease in ABCA1-mediated cholesterol efflux occurred despite an increase in ABCA1 expression. In contrast, DSC1 expression decreased during the differentiation. DSC1 is a negative regulator of the ABCA1-mediated efflux pathway and a DSC1-targeting agent, docetaxel showed high potency and efficacy in promoting ABCA1-mediated cholesterol efflux in THP-1 macrophages. These data suggest that pharmacological targeting of DSC1 may be more effective than increasing ABCA1 expression in promoting macrophage cholesterol efflux. In summary, the comparison of THP-1 macrophage subtypes in varying degrees of differentiation provided new insights into cholesterol metabolism in macrophages and allowed us to identify a viable target DSC1 for the promotion of cholesterol efflux in differentiated macrophages. Docetaxel and other pharmacological strategies targeting DSC1 may hold significant potential for reducing atherogenic cholesterol deposition.
巨噬细胞处理沉积在动脉粥样硬化斑块中的胆固醇的能力取决于它们激活胆固醇流出途径的能力。为了开发旨在促进巨噬细胞胆固醇流出的抗动脉粥样硬化疗法，人们对THP-1单核细胞衍生的巨噬细胞中的胆固醇代谢进行了广泛研究，但单核细胞的内在敏感性以及缺乏将THP-1单核细胞分化为巨噬细胞的标准化程序，使得在不同研究中难以以相同或相似的分化程度利用THP-1巨噬细胞。这种变异性导致人们对分化如何影响胆固醇代谢缺乏了解，在此我们回顾并研究THP-1分化对胆固醇流出的影响。THP-1的分化程度与ATP结合盒A1（ABCA1）转运蛋白介导的胆固醇流出呈负相关。尽管ABCA1表达增加，但ABCA1介导的胆固醇流出仍出现与分化相关的下降。相反，DSC1表达在分化过程中降低。DSC1是ABCA1介导的流出途径的负调节因子，一种靶向DSC1的药物多西他赛在促进THP-1巨噬细胞中ABCA1介导的胆固醇流出方面显示出高效能和有效性。这些数据表明，在促进巨噬细胞胆固醇流出方面，对DSC1进行药物靶向可能比增加ABCA1表达更有效。总之，对不同分化程度的THP-1巨噬细胞亚型进行比较，为巨噬细胞中的胆固醇代谢提供了新的见解，并使我们能够确定一个可行的促进分化巨噬细胞中胆固醇流出的靶点DSC1。多西他赛和其他靶向DSC1的药理策略在减少致动脉粥样硬化胆固醇沉积方面可能具有巨大潜力。
