泛素连接酶IDOL在胆固醇代谢中的作用和机制研究进展

The role and mechanism of ubiquitin ligase IDOL in cholesterol metabolism

胆固醇代谢平衡对细胞和机体的生命活动至关重要.细胞摄取胆固醇的方式之一是低密度脂蛋白受体(low-density lipoprotein receptor,LDLR)介导的低密度脂蛋白内吞;LDLR功能缺陷可导致高脂血症,诱发动脉粥样硬化等心血管疾病.LDLR蛋白稳定性受前蛋白转化酶枯草杆菌蛋白酶9和低密度脂蛋白受体诱导型降解子(inducible degrader of the LDLR,IDOL)调节.IDOL是一种泛素连接酶,能被肝脏X受体转录激活,泛素化LDLR,使其在溶酶体降解.IDOL还能作用于LDLR家族蛋白——极低密度脂蛋白受体与载脂蛋白E(apolipoprotein E,APOE)受体2,参与调控大脑APOE的水平.本文综述了IDOL的结构,其调控LDLR的机制、在转录和转录后水平被调控的机制以及其在心血管疾病及阿尔茨海默病中发挥的作用.这些有关IDOL的最新研究进展可能为上述疾病的治疗提供潜在靶点.

Cholesterol homeostasis plays an important role in maintaining proper cellular and systemic functions.A means for the cell to acquire cholesterol is low-density lipoprotein receptor(LDLR)-mediated uptake of low-density lipoprotein.Dysfunction of LDLR leads to hypercholesterolemia that ultimately contributes to cardiovascular disease such as atherosclerosis.The stability of LDLR protein is regulated by proprotein convertase subtilisin/kexin type 9 and inducible degrader of the LDLR(IDOL).As an E3 ubiquitin ligase,IDOL is subjected to transcriptional regulation by liver X receptor.It can ubiquitylate LDLR and leads to its degradation in the lysosome.IDOL also mediates the degradation of other LDLR family members including very low-density lipoprotein receptor and apolipoprotein E receptor 2,thus regulating apolipoprotein E levels in the brain.This review summarizes the most recent knowledge about IDOL,from the structure,the mechanism on regulating LDLR,to the transcriptional and post-transcriptional regulation of IDOL,as well as its roles in cardiovascular disease and Alzheimer’s disease.These research advances may provide potential therapeutic targets for treating the aforementioned diseases.