Nocito Laura, Kleckner Amber S, Yoo Elsia J, Jones Iv Albert R, Liesa Marc, Corkey Barbara E
Department of Medicine, Boston University, Boston, Massachusetts, United States of America.
PLoS One. 2015 Mar 27;10(3):e0122818. doi: 10.1371/journal.pone.0122818. eCollection 2015.
Circulating redox state changes, determined by the ratio of reduced/oxidized pairs of different metabolites, have been associated with metabolic diseases. However, the pathogenic contribution of these changes and whether they modulate normal tissue function is unclear. As alterations in hepatic gluconeogenesis and glycogen metabolism are hallmarks that characterize insulin resistance and type 2 diabetes, we tested whether imposed changes in the extracellular redox state could modulate these processes. Thus, primary hepatocytes were treated with different ratios of the following physiological extracellular redox couples: β-hydroxybutyrate (βOHB)/acetoacetate (Acoc), reduced glutathione (GSH)/oxidized glutathione (GSSG), and cysteine/cystine. Exposure to a more oxidized ratio via extracellular βOHB/Acoc, GSH/GSSG, and cysteine/cystine in hepatocytes from fed mice increased intracellular hydrogen peroxide without causing oxidative damage. On the other hand, addition of more reduced ratios of extracellular βOHB/Acoc led to increased NAD(P)H and maximal mitochondrial respiratory capacity in hepatocytes. Greater βOHB/Acoc ratios were also associated with decreased β-oxidation, as expected with enhanced lipogenesis. In hepatocytes from fasted mice, a more extracellular reduced state of βOHB/Acoc led to increased alanine-stimulated gluconeogenesis and enhanced glycogen synthesis capacity from added glucose. Thus, we demonstrated for the first time that the extracellular redox state regulates the major metabolic functions of the liver and involves changes in intracellular NADH, hydrogen peroxide, and mitochondrial respiration. Because redox state in the blood can be communicated to all metabolically sensitive tissues, this work confirms the hypothesis that circulating redox state may be an important regulator of whole body metabolism and contribute to alterations associated with metabolic diseases.
由不同代谢物的还原型/氧化型对的比例所决定的循环氧化还原状态变化，已与代谢性疾病相关联。然而，这些变化的致病作用以及它们是否调节正常组织功能尚不清楚。由于肝脏糖异生和糖原代谢的改变是胰岛素抵抗和2型糖尿病的特征性标志，我们测试了细胞外氧化还原状态的人为改变是否能调节这些过程。因此，原代肝细胞用以下生理细胞外氧化还原对的不同比例进行处理：β-羟基丁酸酯（βOHB）/乙酰乙酸（Acoc）、还原型谷胱甘肽（GSH）/氧化型谷胱甘肽（GSSG）和半胱氨酸/胱氨酸。在喂食小鼠的肝细胞中，通过细胞外βOHB/Acoc、GSH/GSSG和半胱氨酸/胱氨酸暴露于更氧化的比例会增加细胞内过氧化氢，但不会造成氧化损伤。另一方面，添加更还原比例的细胞外βOHB/Acoc会导致肝细胞中NAD(P)H增加和最大线粒体呼吸能力增强。更高的βOHB/Acoc比例也与β-氧化减少有关，正如预期的那样，脂肪生成增强。在禁食小鼠的肝细胞中，更细胞外还原状态的βOHB/Acoc会导致丙氨酸刺激的糖异生增加，并增强从添加的葡萄糖合成糖原的能力。因此，我们首次证明细胞外氧化还原状态调节肝脏的主要代谢功能，并涉及细胞内NADH、过氧化氢和线粒体呼吸的变化。由于血液中的氧化还原状态可以传递给所有对代谢敏感的组织，这项工作证实了循环氧化还原状态可能是全身代谢的重要调节因子，并导致与代谢性疾病相关的改变这一假设。
