Montreal Heart Institute and Department of Nutrition and Medicine, Université de Montréal, Canada H1T 1C8.
J Mol Cell Cardiol. 2013 Feb;55:92-100. doi: 10.1016/j.yjmcc.2012.11.008. Epub 2012 Nov 28.
Glutamine, the most abundant amino acid in plasma, has attracted considerable interest for its cardioprotective properties. The primary effect of glutamine in the heart is commonly believed to be mediated via its anaplerotic metabolism to citric acid cycle (CAC) intermediates; however, there is little direct evidence to support this concept. Another potential candidate is the hexosamine biosynthetic pathway (HBP), which has recently been shown to modulate cardiomyocyte function and metabolism. Therefore, the goal of this study was to evaluate the contribution of anaplerosis and the HBP to the acute metabolic effects of glutamine in the heart. Normoxic ex vivo working rat hearts were perfused with (13)C-labeled substrates to assess relevant metabolic fluxes either with a physiological mixture of carbohydrates and a fatty acid (control) or under conditions of restricted pyruvate anaplerosis. Addition of a physiological concentration of glutamine (0.5mM) had no effect on contractile function of hearts perfused under the control condition, but improved that of hearts perfused under restricted pyruvate anaplerosis. Changes in CAC intermediate concentrations as well as (13)C-enrichment from [U-(13)C]glutamine did not support a major role of glutamine anaplerosis under any conditions. Under the control condition, however, glutamine significantly increased the contribution of exogenous oleate to β-oxidation, 1.6-fold, and triglyceride formation, 2.8-fold. Glutamine had no effect on malonyl-CoA or AMP kinase activity levels; however, it resulted in a higher plasma membrane level of the fatty acid transporter CD36. These metabolic effects of glutamine were reversed by azaserine, which inhibits glucose entry into the HPB. Our results reveal a metabolic role of physiological concentration of glutamine in the healthy working heart beyond anaplerosis. This role appears to involve the HBP and regulation of fatty acid entry and metabolism via CD36. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism".
谷氨酰胺是血浆中含量最丰富的氨基酸，因其具有心脏保护特性而引起了相当大的关注。谷氨酰胺在心脏中的主要作用通常被认为是通过其补料代谢为柠檬酸循环 (CAC) 中间体介导的；然而，几乎没有直接证据支持这一概念。另一个潜在的候选者是己糖胺生物合成途径 (HBP)，最近已显示其可调节心肌细胞的功能和代谢。因此，本研究的目的是评估补料和 HBP 对谷氨酰胺在心脏中的急性代谢作用的贡献。在正常氧合的离体工作大鼠心脏中用（13）C 标记的底物进行灌注，以评估相关代谢通量，要么用碳水化合物和脂肪酸的生理混合物（对照），要么在丙酮酸补料受限的条件下进行。添加生理浓度的谷氨酰胺（0.5mM）对在对照条件下灌注的心脏的收缩功能没有影响，但改善了在丙酮酸补料受限的情况下灌注的心脏的收缩功能。在任何条件下，CAC 中间浓度的变化以及来自[U-（13）C]谷氨酰胺的（13）C 丰度都不支持谷氨酰胺补料的主要作用。然而，在对照条件下，谷氨酰胺显著增加了外源性油酸向β-氧化的贡献，增加了 1.6 倍，增加了甘油三酯的形成，增加了 2.8 倍。谷氨酰胺对丙二酰辅酶 A 或 AMP 激酶活性水平没有影响；然而，它导致脂肪酸转运蛋白 CD36 的质膜水平更高。谷氨酰胺的这些代谢作用被抑制葡萄糖进入 HBP 的放线菌氨酸所逆转。我们的结果揭示了健康工作心脏中生理浓度谷氨酰胺的代谢作用超出了补料的作用。这种作用似乎涉及 HBP 和通过 CD36 调节脂肪酸的进入和代谢。本文是题为“关注心脏代谢”的特刊的一部分。
