低密度脂蛋白受体转运的调节机制

Regulatory mechanism of low density lipoprotein receptor trafficking

摘要:

肝细胞表面的低密度脂蛋白受体所介导的脂蛋白颗粒吞噬是机体清除循环中低密度脂蛋白的主要途径,在维持体内胆固醇代谢稳态中扮演极其重要的角色。本文简要回顾了低密度脂蛋白受体转运的不同环节,包括内吞、分选、受体分子的降解通道或再循环通道,以及各环节的主要调控因子,总结了相关领域的最新前沿进展。目前,间接靶向低密度脂蛋白受体转录调控的药物开发(他汀类药物)及靶向低密度脂蛋白受体进入降解通道的药物开发[前蛋白转化酶枯草溶菌素9(PCSK9)抑制剂]均取得了巨大成功。尽管如此,人们对调控低密度脂蛋白受体转运的分子机制了解尚不完全,特别是对低密度脂蛋白受体的胞内再循环过程及相关的信号传导机制尚需更多研究。因此对这些机制的进一步深入研究可以为发现治疗高胆固醇血症的新靶点提供思路。

Abstract:

Phagocytosis of lipoprotein particles mediated by low density lipoprotein receptors on the surface of hepatocytes is the main pathway for the body to clear circulating low density lipoprotein, and plays a pivotal role in maintaining the homeostasis of cholesterol metabolism in the body. This article briefly reviewed the different links of low density lipoprotein receptor trafficking, including endocytosis, sorting, degradation or recycling channels of receptor molecules, and the main regulatory factors of each link, and summarized the latest advances in related fields. At present, the development of drugs indirectly targeting low density lipoprotein receptor transcriptional regulation (statins) and drugs targeting low density lipoprotein receptor degradation (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors) have achieved tremendous success. However, our understanding of the molecular mechanisms regulating low density lipoprotein receptor trafficking remains to be incomplete, especially the intracellular recycling processes and the related signaling mechanisms need more research. It is anticipated that further in-depth research in these areas may foster the discovery of new targets for the treatment of hypercholesterolemia in the future.