Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
Keenan Research Centre for Biomedical Science, Unity Health Toronto, Toronto, Canada.
Curr Atheroscler Rep. 2023 Aug;25(8):457-465. doi: 10.1007/s11883-023-01118-x. Epub 2023 Jun 26.
The accumulation of LDL in the arterial intima is an initiating event in atherosclerosis. After decades of controversy, it is now clear that transcytosis of LDL across an intact endothelial monolayer contributes to its intimal deposition. We review recent observations in this field and address the question of whether LDL transcytosis can be manipulated therapeutically.
The development of a live-cell imaging method for studying transcytosis using total internal reflection fluorescence (TIRF) microscopy has catalyzed recent discoveries. LDL transcytosis is mediated by SR-BI and ALK1. Estrogen down-regulates SR-BI and inhibits LDL transcytosis, while the nuclear structural protein HMGB1 promotes LDL transcytosis. LDL transcytosis by ALK1 is independent of the receptor's kinase activity and is antagonized by BMP9, ALK1's canonical ligand. Inflammation stimulates LDL transcytosis. Identifying the function and mechanisms of LDL transcytosis may ultimately permit its therapeutic manipulation.
LDL 在动脉内膜中的积累是动脉粥样硬化的起始事件。经过几十年的争议，现在很清楚，LDL 通过完整的内皮单层的转胞吞作用有助于其内膜沉积。我们综述了该领域的最新观察结果，并探讨了 LDL 转胞吞作用是否可以进行治疗性操作的问题。
使用全内反射荧光 (TIRF) 显微镜研究转胞吞作用的活细胞成像方法的发展促进了最近的发现。LDL 转胞吞作用由 SR-BI 和 ALK1 介导。雌激素下调 SR-BI 并抑制 LDL 转胞吞作用，而核结构蛋白 HMGB1 促进 LDL 转胞吞作用。ALK1 的 LDL 转胞吞作用不依赖于受体的激酶活性，并被其经典配体 BMP9 拮抗。炎症刺激 LDL 转胞吞作用。鉴定 LDL 转胞吞作用的功能和机制最终可能使其治疗性操作成为可能。
