Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain
Heptanoate as a neural fuel: energetic and neurotransmitter precursors in normal and glucose transporter I-deficient (G1D) brain
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DOI：
10.1038/jcbfm.2012.151
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发表时间：
2013-02-01
影响因子：
6.3
通讯作者：
Pascual, Juan M.
中科院分区：
文献类型：
--
作者：
Marin-Valencia, Isaac;Good, Levi B.;Pascual, Juan M.
据推测，三庚烷可以通过为三羧酸循环提供乙酰辅酶A产生能量和丙酰辅酶A补充循环中间体来改善癫痫发作。这些潜在的影响在其他与葡萄糖代谢受损相关的疾病中也可能很重要，因为葡萄糖除了供应乙酰辅酶A外，还供应丙酮酸，丙酮酸通过羧化来满足生物合成需求。在葡萄糖转运蛋白I型缺乏(G1D)的患者中，生酮饮食脂肪(乙酰辅酶A的来源之一)可以减少癫痫发作，但其他症状仍然存在，这为研究庚酸代谢提供了动力。本工作采用C-13核磁共振波谱、气相色谱-质谱(GC-MS)和液质联用(LC-MS)技术研究了[5，6，7-C-13(3)]庚酸酯在正常小鼠脑和G1D小鼠体内的代谢。在两组中，血糖都在C-13中浓缩，证实了庚酸的糖异生作用。与正常小鼠相比，G1D小鼠大脑中的乙酰辅酶A和谷氨酰胺水平显著升高。此外，与谷氨酸相比，两组动物的脑谷氨酰胺浓度和C-13丰度也更高，这表明庚酸和/或C5酮主要由胶质细胞代谢。这些结果揭示了庚酸在正常和葡萄糖缺乏的大脑中的代谢机制，并鼓励进一步的研究来阐明其在能量代谢紊乱中潜在的抗癫痫作用。《脑血流与代谢杂志》(2013年)33期，第175-182期；doi：10.1038/jcbfm.2012.151；2012年10月17日在线发表
It has been postulated that triheptanoin can ameliorate seizures by supplying the tricarboxylic acid cycle with both acetyl-CoA for energy production and propionyl-CoA to replenish cycle intermediates. These potential effects may also be important in other disorders associated with impaired glucose metabolism because glucose supplies, in addition to acetyl-CoA, pyruvate, which fulfills biosynthetic demands via carboxylation. In patients with glucose transporter type I deficiency (G1D), ketogenic diet fat (a source only of acetyl-CoA) reduces seizures, but other symptoms persist, providing the motivation for studying heptanoate metabolism. In this work, metabolism of infused [5,6,7-C-13(3)]heptanoate was examined in the normal mouse brain and in G1D by C-13-nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry (GC-MS), and liquid chromatography-mass spectrometry (LC-MS). In both groups, plasma glucose was enriched in C-13, confirming gluconeogenesis from heptanoate. Acetyl-CoA and glutamine levels became significantly higher in the brain of G1D mice relative to normal mice. In addition, brain glutamine concentration and C-13 enrichment were also greater when compared with glutamate in both animal groups, suggesting that heptanoate and/or C5 ketones are primarily metabolized by glia. These results enlighten the mechanism of heptanoate metabolism in the normal and glucose-deficient brain and encourage further studies to elucidate its potential antiepileptic effects in disorders of energy metabolism. Journal of Cerebral Blood Flow & Metabolism (2013) 33, 175-182; doi:10.1038/jcbfm.2012.151; published online 17 October 2012