Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Program in Neuroscience and Behavior Disorders, Duke-NUS Medical School, Singapore.
IUBMB Life. 2022 Aug;74(8):826-841. doi: 10.1002/iub.2662. Epub 2022 Jul 14.
Cholesterol is a ubiquitous and essential component of cellular membranes, as it regulates membrane structure and fluidity. Furthermore, cholesterol serves as a precursor for steroid hormones, oxysterol, and bile acids, that are essential for maintaining many of the body's metabolic processes. The biosynthesis and excretion of cholesterol is tightly regulated in order to maintain homeostasis. Although virtually all cells have the capacity to make cholesterol, the liver and brain are the two main organs producing cholesterol in mammals. Once produced, cholesterol is transported in the form of lipoprotein particles to other cell types and tissues. Upon formation of the blood-brain barrier (BBB) during embryonic development, lipoproteins cannot move between the central nervous system (CNS) and the rest of the body. As such, cholesterol biosynthesis and metabolism in the CNS operate autonomously without input from the circulation system in normal physiological conditions. Nevertheless, similar regulatory mechanisms for maintaining cholesterol homeostasis are utilized in both the CNS and peripheral systems. Here, we discuss the functions and metabolism of cholesterol in the CNS. We further focus on how different CNS cell types contribute to cholesterol metabolism, and how ApoE, the major CNS apolipoprotein, is involved in normal and pathophysiological functions. Understanding these basic mechanisms will aid our ability to elucidate how CNS cholesterol dysmetabolism contributes to neurogenerative diseases.
胆固醇是细胞膜中普遍存在且必不可少的成分，因为它可以调节膜结构和流动性。此外，胆固醇还是类固醇激素、氧化固醇和胆汁酸的前体，这些物质对于维持身体许多代谢过程至关重要。胆固醇的生物合成和排泄受到严格调控，以维持体内平衡。尽管几乎所有细胞都有合成胆固醇的能力，但肝脏和大脑是哺乳动物中产生胆固醇的两个主要器官。一旦合成，胆固醇就会以脂蛋白颗粒的形式运输到其他细胞类型和组织中。在胚胎发育过程中形成血脑屏障（BBB）后，脂蛋白不能在中枢神经系统（CNS）和身体其他部位之间移动。因此，在正常生理条件下，中枢神经系统中的胆固醇生物合成和代谢是自主进行的，而不受循环系统的影响。然而，在中枢神经系统和外周系统中都利用了类似的维持胆固醇平衡的调节机制。在这里，我们讨论了胆固醇在中枢神经系统中的功能和代谢。我们进一步关注不同中枢神经系统细胞类型如何参与胆固醇代谢，以及载脂蛋白 E（ApoE）——主要的中枢神经系统载脂蛋白——如何参与正常和病理生理功能。了解这些基本机制将有助于我们阐明中枢神经系统胆固醇代谢紊乱如何导致神经退行性疾病。
