Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier
Nitric oxide isoenzymes regulate lipopolysaccharide-enhanced insulin transport across the blood-brain barrier
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DOI：
10.1210/en.2007-1091
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发表时间：
2008-04-01
期刊：
影响因子：
4.8
通讯作者：
Vo, Than Q.
中科院分区：
文献类型：
--
作者：
Banks, William A.;Dohgu, Shinya;Vo, Than Q.
胰岛素通过血脑屏障(BBB)转运在中枢神经系统内有许多作用。胰岛素的运输不是一成不变的，而是受到肥胖和炎症的影响。来自革兰氏阴性菌细胞壁的脂多糖(LPS)可促进胰岛素跨血脑屏障的转运，但也会释放一氧化氮(NO)，后者反对内毒素增强的胰岛素转运。在此，我们确定了一氧化氮合酶(NOS)在介导内毒素对胰岛素血脑屏障转运影响中的作用。3种一氧化氮合酶同工酶均可在体内被内毒素刺激。内皮一氧化氮合酶和诱导型一氧化氮合酶共同介导内毒素促进的胰岛素转运，而神经元型一氧化氮合酶(NNOS)拮抗内毒素促进的胰岛素转运。除了纹状体和顶叶皮质、海马体和延髓以外的大多数脑区都发现了这种双重的NOS活动模式，纹状体对内毒素没有反应，顶叶皮质、海马体和脑桥延髓对nNOS抑制没有反应。体外脑内皮细胞(BEC)单层血脑屏障模型的研究表明，内毒素不直接影响胰岛素转运，而NO则抑制胰岛素转运。提示内毒素和一氧化氮合酶对胰岛素转运的刺激作用是通过神经血管单位的细胞而不是内皮细胞来实现的。同工酶的蛋白质和mRNA水平表明，内毒素的作用主要是翻译后的。总之，内毒素通过调节一氧化氮合酶同工酶活性来影响胰岛素跨血脑屏障的转运。内皮型一氧化氮合酶和诱导型一氧化氮合酶释放的NO间接促进胰岛素转运，而nNOS释放的一氧化氮直接作用于内皮细胞抑制胰岛素转运。
Insulin transported across the blood-brain barrier (BBB) has many effects within the central nervous system. Insulin transport is not static but altered by obesity and inflammation. Lipopolysaccharide (LPS), derived from the cell walls of Gram-negative bacteria, enhances insulin transport across the BBB but also releases nitric oxide (NO), which opposes LPS-enhanced insulin transport. Here we determined the role of NO synthase (NOS) in mediating the effects of LPS on insulin BBB transport. The activity of all three NOS isoenzymes was stimulated in vivo by LPS. Endothelial NOS and inducible NOS together mediated the LPS-enhanced transport of insulin, whereas neuronal NOS (nNOS) opposed LPS-enhanced insulin transport. This dual pattern of NOS action was found in most brain regions with the exception of the striatum, which did not respond to LPS, and the parietal cortex, hippocampus, and pons medulla, which did not respond to nNOS inhibition. In vitro studies of a brain endothelial cell (BEC) monolayer BBB model showed that LPS did not directly affect insulin transport, whereas NO inhibited insulin transport. This suggests that the stimulatory effect of LPS and NOS on insulin transport is mediated through cells of the neurovascular unit other than BECs. Protein and mRNA levels of the isoenzymes indicated that the effects of LPS are mainly post-translational. In conclusion, LPS affects insulin transport across the BBB by modulating NOS isoenzyme activity. NO released by endothelial NOS and inducible NOS acts indirectly to stimulate insulin transport, whereas NO released by nNOS acts directly on BECs to inhibit insulin transport.