浙江大学医学院Dante Neculai课题组的一项最新研究发现鞘氨醇-1-磷酸信号激活E-Syt1促进高密度脂蛋白来源的胆固醇运输。2025年5月28日，国际知名学术期刊《自然—细胞生物学》发表了这一成果。

在这里，课题组发现了一个通过内质网（ER）和质膜（PM）之间的膜接触位点协调HDL衍生胆固醇运输的信号级联。研究小组发现HDL-驻地鞘氨醇-1-磷酸（S1P）激活S1P受体3及其相关的G蛋白αq，导致磷脂酶-C-β3介导的磷脂酰肌醇4,5-二磷酸水解和细胞质钙升高。这个钙信号触发扩展突触蛋白1快速募集到ER-PM膜接触部位。遗传或药理学破坏这一途径会损害高密度脂蛋白来源的胆固醇向细胞内区室的非囊性转移。他们的发现揭示了HDL结合到细胞表面是如何通过S1P信号改变ER-PM膜接触位点动力学的。这确保了高密度脂蛋白胆固醇的有效卸载和再分配，以支持类固醇和胆汁酸的合成。

据介绍，来自高密度脂蛋白（HDL）的胆固醇在类固醇生成细胞和产胆细胞中迅速重新分配到细胞内，但控制这一重要运输过程的分子机制尚不清楚。

附：英文原文

Title: Sphingosine-1-phosphate signalling activates E-Syt1 to facilitate HDL-derived cholesterol transport

Author: Xu, Zizhen, Meng, Ying, St-Germain, Jonathan, Afshari, Arezoo, Dixon, Charneal L., Heybrock, Saskia, Zhao, Qiang, Weng, Xialian, Chen, Jishun, Collins, Richard, Hu, Hu, Zhou, Quan, Sun, Qiming, Xu, Pinglong, Liu, Wei, Saftig, Paul, Raught, Brian, Fairn, Gregory D., Neculai, Dante

Issue&Volume: 2025-05-28

Abstract: Cholesterol derived from high-density lipoprotein (HDL) is rapidly redistributed to intracellular compartments in steroidogenic and bile-producing cells, but the molecular mechanisms governing this essential transport process remain poorly understood. Here we uncover a signalling cascade coordinating HDL-derived cholesterol transport through membrane contact sites between the endoplasmic reticulum (ER) and plasma membrane (PM). We find that HDL-resident sphingosine-1-phosphate (S1P) activates S1P receptor 3 and its associated G protein αq, leading to phospholipase-C-β3-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate and an elevation in cytosolic calcium. This calcium signal triggers the rapid recruitment of Extended-Synaptotagmin 1 to ER–PM membrane contact sites. Genetic or pharmacological disruption of this pathway impairs the non-vesicular transfer of HDL-derived cholesterol to intracellular compartments. Our findings reveal how HDL binding to the cell surface alters ER–PM membrane contact site dynamics through S1P signalling. This ensures efficient offloading and redistribution of HDL cholesterol to support steroid and bile acid synthesis.

DOI: 10.1038/s41556-025-01665-2

Source: https://www.nature.com/articles/s41556-025-01665-2