Fatty acid regulation of glucose metabolism in the intact beating rat heart assessed by carbon-13 NMR spectroscopy: the critical role of pyruvate dehydrogenase.
Fatty acid regulation of glucose metabolism in the intact beating rat heart assessed by carbon-13 NMR spectroscopy: the critical role of pyruvate dehydrogenase.
复制标题
通过碳 13 NMR 光谱评估完整跳动大鼠心脏中葡萄糖代谢的脂肪酸调节：丙酮酸脱氢酶的关键作用。
DOI：
10.1016/0022-2828(89)90787-6
复制
发表时间：
1989
影响因子：
5
通讯作者：
Gerstenblith,G
中科院分区：
文献类型：
--
作者：
Weiss,RG;Chacko,VP;Gerstenblith,G
虽然心肌能够利用葡萄糖和脂肪酸底物，但在正常灌注条件下，脂肪酸存在时葡萄糖代谢受到抑制。用8.5T的13 C和31 P核磁共振技术和13 C富集底物研究了脂肪酸对大鼠完整心脏葡萄糖利用的调节作用。在[1-13 C]葡萄糖和胰岛素灌注期间，13 C出现在丙氨酸、乳酸盐和谷氨酸盐同位素异构体中，分别指示通过丙酮酸盐和葡萄糖支持的三羧酸（TCA）循环氧化的糖酵解通量。加入1 mM己酸后，[1-13 C]葡萄糖代谢通过己糖激酶和磷酸果糖激酶反应进行，如[3-13 C]丙氨酸和[3-13 C]乳酸盐的继续产生所证明的，但在丙酮酸脱氢酶（PDH）反应中完全被抑制，如谷氨酸盐同位素异构体中缺乏13 C标记所证明的。PDH的这种抑制与PCr ATP水平的增加有关，并且很容易通过去除己酸来逆转。添加二氯乙酸，5毫米，这增加了活性形式的PDH，脂肪酸和葡萄糖的灌流液reinstituted碳通量通过PDH反应，表明脂肪酸的PDH通量停止的机制是通过可逆的失活的PDH酶复合物。因此，脂肪酸调节葡萄糖代谢的抑制点和作用机制可以在完整的跳动心脏中用13 C和31 P NMR连续和非破坏性地研究，并且在该模型中主要归因于可逆的PDH酶失活。
Although the myocardium is capable of utilizing both glucose and fatty acid substrates, glucose metabolism is inhibited in the presence of fatty acid during normal perfusion conditions. Fatty acid regulation of glucose utilization in intact beating rat hearts was studied with 13 C-enriched substrates and 13 C and 31 P NMR spectroscopy at 8.5 T. During [1-13 C] glucose and insulin perfusion, the 13 C appeared in alanine, lactate and the glutamate isotopomers, indicating glycolytic flux through pyruvate and glucose-supported tricarboxylic acid (TCA) cycle oxidation, respectively. Following the addition of hexanoic acid, 1 m m,[1-13 C] glucose metabolism proceeded through the hexokinase and phosphofructokinase reactions, as evidenced by continued production of [3-13 C] alanine and [3-13 C] lactate, but was completely inhibited at the pyruvate dehydrogenase (PDH) reaction as evidenced by a lack of appearance of the 13 C label in the glutamate isotopomers. This inhibition of PDH was associated with increased PCr ATP levels and was readily reversed by removal of hexanoic acid. Addition of dichloroacetate, 5 m m, which increases the active form of PDH, to fatty acid and glucose containing perfusate reinstituted carbon flux through the PDH reaction, indicating that the mechanism of fatty acid cessation of PDH flux is by reversible inactivation of the PDH enzyme complex. Thus the point of inhibition and mechanism of action of fatty acid modulation of glucose metabolism can be continuously and non-destructively studied in the intact beating heart with 13 C and 31 P NMR and is primarily attributable, in this model, to reversible PDH enzyme inactivation.