ALTERATIONS IN LIPID METABOLISM IN THE NERVOUS SYSTEM BY

神经系统脂质代谢的改变

• 批准号: 6097592
• 负责人: Hee-Yong Kim
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6097592
• 关键词: brain metabolism; eicosanoid metabolism; electrospray ionization mass spectrometry; enzyme activity; ethanol; fatty acid metabolism; laboratory rat; membrane lipids; microsomes; neuropharmacology; omega 3 fatty acid; phosphatidylcholines; phosphatidylserines; phospholipids; pineal body; serotonin receptor; unsaturated fatty acids

The principal objective of this study is to elucidate metabolic and biological functions of polyunsaturated fatty acids, docosahexaenoic acid (22:6n3) and arachidonic acid (20:4n6) in the nervous system with particular reference to their modulation by ethanol. We have previously found that 22:6n3 promotes the accumulation of phosphatidylserine (PS), which is thought to be involved in growth factor signaling leading to cell survival. Preliminary results obtained by the differential sedimentation assay indicated that polyunsaturated fatty acids, 20:4n6 and 22:6n3, prevented the apoptotic cell death of both Neuro 2A and PC-12 cells. During this period, the effect of polyunsaturates on the survival of neuronal cells was further investigated along with the underlying mechanisms of this effect. The apoptotic cell death induced by serum deprivation was confirmed by DNA ladder formation and by Hoechst staining. Docosahexaenoic acid significantly decreased DNA ladder formation and chromatin condensation. However, 22:6n3 exerted its effect only after enrichment of this fatty acid in membrane phospholipids, especially in the aminophospholipids, phosphatidylethanolamine (PE) and phosphatidylserine (PS). These data suggest that 22:6n3 as a membrane phospholipid constituent, especially in aminophospholipids, may be important for the protective effect. The analysis by RT-PCR and immunoblotting indicated that the prevention of apoptosis by 22:6n3 enrichment was mediated by the down regulation of CPP-32 at both gene and protein levels but not by over expression of bcl-2. We also found during this period that n-3 deficiency decreased melatonin biosynthesis significantly, suggesting a role of n-3 polyunsaturated fatty acids in pineal biochemical functions.

这项研究的主要目的是阐明 多不饱和脂肪酸的代谢和生物学功能， 在 神经系统特别参考其调节 乙醇。我们以前已经发现22：6n3促进了 磷脂酰丝氨酸（PS）的积累，被认为是 参与生长因子信号传导导致细胞存活。 通过差分沉积测定法获得的初步结果 表明多不饱和脂肪酸，20：4n6和22：6n3， 防止了Neuro 2a和PC-12的凋亡细胞死亡 细胞。在此期间，多不饱和的影响对 神经元细胞的存活与 这种作用的基本机制。凋亡细胞死亡 通过DNA梯子证实了血清剥夺诱导的 形成和通过染色。二十二烯酸 显着降低了DNA梯子形成和染色质 缩合。但是，22：6n3仅在 这种脂肪酸在膜磷脂中富集，尤其是 在氨基磷脂中，磷脂酰乙醇胺（PE）和 磷脂酰丝氨酸（PS）。这些数据表明22：6n3是 膜磷脂成分，特别是 氨基磷脂对于保护作用可能很重要。 RT-PCR和免疫印迹的分析表明 预防22：6n3富集的凋亡是由 下调CPP-32在基因和蛋白质水平上的调节 通过过度表达Bcl-2。我们还发现在此期间 N-3缺乏症显着降低了褪黑激素的生物合成， 提出N-3多不饱和脂肪酸在松果体中的作用 生化功能。