苏黎世技术大学Martin Fussenegger研究小组开发出控制实验性血脂异常的闭环胆固醇分流。这一研究成果发表在2025年9月18日出版的国际学术期刊《细胞—代谢》上。

为了应对血脂异常的挑战，研究团队提出了胆固醇稳态和调节模块（CHARM），这是一个设计的基因电路，用于实时感知胆固醇水平升高，并加强先天胆固醇稳态机制。该电路结合了一个由Krüppel相关盒（KRAB）结构域和一个修饰的甾醇调节元件（SRE）结合蛋白1a（SREBP1a）组成的定制融合蛋白作为传感器平台，以及一个合成表达模块，该模块包含一个组成启动子下游的SRE操作位点，该模块能够以闭环方式生产治疗性蛋白以降低低密度脂蛋白胆固醇（LDL-C）水平。在高胆固醇血症小鼠体内植入微胶囊化的CHARM转基因人细胞，可迅速恢复并随后稳定维持胆固醇稳态。

研究人员表示，高胆固醇血症是一种由脂质代谢失调引起的复杂代谢紊乱，是动脉粥样硬化、冠状动脉疾病和心肌梗死的重要危险因素。

附：英文原文

Title: A closed-loop cholesterol shunt controlling experimental dyslipidemia

Author: Gokberk Unal, Yu-Qing Xie, Martin Fussenegger

Issue&Volume: 2025-09-18

Abstract: Hypercholesterolemia is a complex metabolic disorder resulting from dysregulated lipid metabolism and is a significant risk factor for atherosclerosis, coronary artery disease, and myocardial infarction. To address the challenge of dyslipidemia, we present the cholesterol homeostasis and regulation module (CHARM), a designer genetic circuit engineered to sense elevated cholesterol levels in real time and strengthen the innate cholesterol homeostasis machinery. The circuit incorporates a custom fusion protein consisting of the Krüppel-associated box (KRAB) domain and a modified sterol regulatory element (SRE)-binding protein 1a (SREBP1a) as a sensor platform, along with a synthetic expression module containing SRE operator sites downstream of a constitutive promoter that enables the production of a therapeutic protein to reduce low-density lipoprotein cholesterol (LDL-C) levels in a closed-loop fashion. Implantation of microencapsulated CHARM-transgenic human cells in hypercholesterolemic mice rapidly restored and subsequently stably maintained cholesterol homeostasis.

DOI: 10.1016/j.cmet.2025.08.011

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(25)00384-5