Wang Ning-Qi, Sun Pei-Xiang, Shen Qi-Qi, Deng Meng-Yan
Institute of Clinical Pharmacology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, China.
Institute of Clinical Medicine, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, 450001, China.
Mol Neurobiol. 2025 May;62(5):6283-6307. doi: 10.1007/s12035-024-04672-w. Epub 2025 Jan 7.
The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.
大脑是人体中胆固醇含量最高的器官。大脑中的胆固醇在维持突触和髓鞘的完整性以确保大脑正常功能方面起着至关重要的作用。胆固醇代谢紊乱与多种中枢神经系统（CNS）疾病密切相关，包括阿尔茨海默病（AD）、亨廷顿舞蹈病（HD）和多发性硬化症（MS）。在本综述中，我们探讨了胆固醇在中枢神经系统中的合成、调节、运输及其功能作用。我们详细讨论了胆固醇稳态失衡与包括AD、HD和MS在内的中枢神经系统疾病之间的关联，强调了胆固醇代谢异常在这些疾病发展中的重要作用。甾醇调节元件结合蛋白2（SREBP2）和肝X受体（LXR）是两个关键的转录因子，分别在胆固醇合成和逆向转运中起核心作用。它们的协同相互作用精细地调节着脑胆固醇代谢的平衡，为预防和治疗中枢神经系统疾病提供了潜在的治疗价值。我们特别强调了病理条件下SREBP2和LXR的改变及其对疾病进展的影响。本综述总结了目前针对这两条途径的治疗药物，希望拓宽中枢神经系统药物开发者的视野，并鼓励对中枢神经系统疾病的SREBP2和LXR相关疗法进行进一步研究。
