High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism
High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism
复制标题
DOI：
10.1096/fj.12-205807
复制
发表时间：
2012-10-01
期刊：
影响因子：
4.8
通讯作者：
Verheijen, Mark H. G.
中科院分区：
文献类型：
--
作者：
Camargo, Nutabi;Brouwers, Jos F.;Verheijen, Mark H. G.
哺乳动物中枢神经系统被认为是自主的脂质代谢。神经胶质细胞，特别是星形胶质细胞，已被证明在脂质合成和分泌中具有高度活性。为了确定星形胶质细胞作为脑中脂质提供者的重要性，我们产生了使用cre/lox技术从星形胶质细胞中删除固醇调节元件结合蛋白（SREBP）裂解激活蛋白（SCAP）的小鼠。SCAP突变小鼠表现为小头畸形，对星形胶质细胞存活无影响。星形胶质细胞中SCAP的缺失导致胆固醇和脂肪酸合成途径的丧失。SCAP突变体表现出进行性运动缺陷、运动障碍和焦虑减少。有趣的是，SCAP突变体显示脑固醇和脂肪酸谱的变化与脂质合成减少以及膳食脂质摄取增加一致。因此，富含胆固醇和单不饱和脂肪酸的高脂肪饮食，而不是富含多不饱和脂肪酸的鱼油饮食，改善了突变小鼠的运动缺陷和存活率。这些观察结果建立了星形胶质细胞在脑脂质代谢中的关键作用，并表明膳食脂质可以挽救星形胶质细胞介导的脂质缺乏。纠正这些神经缺陷的能力表明，脂质补充剂可以作为与星形胶质细胞脂质合成缺陷相关的脑部疾病的治疗方法。Camargo，N.，Brouwers，J.F.，卢什，M.，Gutmann，D. H、Smit，A. B.，Verheijen，M. H. G.高脂饮食改善由星形胶质细胞脂质代谢缺陷引起的神经功能缺损。FASEB J.26，4302-4315（2012）。www.fasebj.org
The mammalian CNS is considered to be autonomous in lipid metabolism. Glial cells, in particular astrocytes, have been shown to be highly active in lipid synthesis and secretion. To determine the importance of astrocytes as lipid providers in the brain, we generated mice in which the sterol regulatory element-binding protein (SREBP) cleavage-activating protein (SCAP) was deleted from astrocytes using cre/lox technology. SCAP mutant mice showed microcephaly, without effects on astrocyte survival. SCAP deletion in astrocytes led to a loss of cholesterol and fatty acid synthesis pathways. SCAP mutants showed progressive motor deficits, dyskinesia, and reduced anxiety. Interestingly, SCAP mutants showed changes in brain sterol and fatty acid profiles that were concordant with reduced lipid synthesis as well as with increased uptake of dietary lipids. Accordingly, a high-fat diet rich in cholesterol and monounsaturated fatty acids, but not a fish oil diet rich in polyunsaturated fatty acids, improved motor deficits and survival of the mutant mice. These observations establish a critical role for astrocytes in brain lipid metabolism and demonstrate that dietary lipids can rescue astrocyte-mediated lipid deficiency. The ability to correct these neurological deficits suggests that lipid supplementation may serve as a treatment for brain disorders associated with defective astrocyte lipid synthesis.-Camargo, N., Brouwers, J. F., Loos, M., Gutmann, D. H., Smit, A. B., Verheijen, M. H. G. High-fat diet ameliorates neurological deficits caused by defective astrocyte lipid metabolism. FASEB J. 26, 4302-4315 (2012). www.fasebj.org