Farooqui Akhlaq A, Ong Wei-Yi, Farooqui Tahira
Department of Molecular Cellular Biochemistry, The Ohio State University, Columbus, OH 43221, USA.
Biochim Biophys Acta. 2010 Aug;1801(8):906-16. doi: 10.1016/j.bbalip.2010.02.002. Epub 2010 Feb 17.
Degradation of glycerophospholipids, sphingolipids and cholesterol in the nucleus modulates neural cell proliferation and differentiation, inflammation, apoptosis, migration, cell adhesion, and intracellular trafficking. Extracellular signals from agonists (neurotransmitters, cytokines, and growth factors) regulate the activity of a key set of lipid-metabolizing enzymes, such as phospholipases, sphingomyelinases, and cholesterol hydroxylases. These enzymes and their downstream targets constitute a complex lipid signaling network with multiple nodes of interaction and cross-regulation through their lipid mediators, which include eicosanoids, docosanoids, diacylglycerols, platelet activating factor, lysophosphatidic acid, ceramide and ceramide 1-phosphate, sphingosine and sphingosine 1-phosphate, and hydroxycholesterols. Receptors for above lipid mediators are localized at the neural cell nucleus. Stimulation of isolated nuclei with these lipids and agonists results in changes in transcriptional regulation of major genes, including c-fos, cylooxygenase-2, secretory phospholipase A(2) and endothelial as well as inducible nitric oxide synthases. Imbalances in signaling network involving above genes may contribute to the pathogenesis of human neurological disorders. In this review, we have attempted to integrate available information on above lipid mediators in the nucleus. In addition, attempts have been made to explain cross-talk among glycerophospholipid-, sphingolipid-, and cholesterol-derived lipid mediators in neural cell death in Alzheimer's disease.
细胞核中甘油磷脂、鞘脂和胆固醇的降解调节神经细胞的增殖与分化、炎症、凋亡、迁移、细胞黏附及细胞内运输。来自激动剂（神经递质、细胞因子和生长因子）的细胞外信号调节一组关键脂质代谢酶的活性，如磷脂酶、鞘磷脂酶和胆固醇羟化酶。这些酶及其下游靶点构成一个复杂的脂质信号网络，通过其脂质介质进行多节点的相互作用和交叉调节，这些脂质介质包括类二十烷酸、二十二碳六烯酸、二酰基甘油、血小板活化因子、溶血磷脂酸、神经酰胺和神经酰胺1-磷酸、鞘氨醇和鞘氨醇1-磷酸以及羟基胆固醇。上述脂质介质的受体定位于神经细胞核。用这些脂质和激动剂刺激分离的细胞核会导致主要基因转录调控的变化，包括c-fos、环氧化酶-2、分泌型磷脂酶A(2)以及内皮型和诱导型一氧化氮合酶。涉及上述基因的信号网络失衡可能导致人类神经疾病的发病机制。在本综述中，我们试图整合关于细胞核中上述脂质介质的现有信息。此外，还尝试解释阿尔茨海默病神经细胞死亡中甘油磷脂、鞘脂和胆固醇衍生的脂质介质之间的相互作用。
