Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice
Glycerol-3-phosphate dehydrogenase 1 deficiency induces compensatory amino acid metabolism during fasting in mice
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DOI：
10.1016/j.metabol.2016.08.005
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发表时间：
2016-11-01
影响因子：
9.8
通讯作者：
Miura, Shinji
中科院分区：
文献类型：
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作者：
Sato, Tomoki;Yoshida, Yuma;Miura, Shinji
背景葡萄糖被用作许多器官的能量来源，并从膳食碳水化合物中获得。然而，当外部能量供应中断时，例如，在禁食期间，保存在肝脏中的碳水化合物和来自其他器官的糖原生成前体用于维持血糖水平。脂肪细胞和骨骼肌中的甘油和糖原生成氨基酸被用作糖原生成前体。甘油-3-磷酸脱氢酶1（GPD 1）是一种存在于细胞溶质中的NAD（+）/NADH依赖性酶，催化甘油-3-磷酸（G3 P）可逆转化为二羟丙酮磷酸（DHAP）。由于G3 P是肝脏中用于葡萄糖生成的底物之一，因此GPD 1将G3 P转化为DHAP对于在禁食期间维持血糖水平至关重要。我们专注于GPD 1，并研究其在禁食期间的胚胎发生中的作用。使用GPD 1缺失模型BALB/cHeA小鼠（HeA小鼠），我们测量了甘油的糖异生作用以及空腹条件下血糖水平的变化。我们还测量了肝脏中与胚胎发生相关的基因表达和骨骼肌中的蛋白质代谢。以BALB/cBy小鼠（By mice）为对照。甘油给药后，HeA小鼠的血糖水平低于By小鼠。虽然GPD 1的缺乏抑制了甘油的生成，但禁食1-4小时后HeA小鼠的血糖水平显著高于By小鼠。HeA小鼠的肌肉蛋白质合成显著低于By小鼠。此外，HeA小鼠的血液丙氨酸水平和丙氨酸在肝脏中的利用率显著高于By小鼠。虽然这些数据表明，缺乏GPD 1抑制从甘油的糖原异生，慢性GPD 1缺乏症可能会诱导一种适应，增强从糖原生成氨基酸的糖原异生。(C)2016 Elsevier Inc. All rights reserved.
Background. Glucose is used as an energy source in many organs and obtained from dietary carbohydrates. However, when the external energy supply is interrupted, e.g., during fasting, carbohydrates preserved in the liver and glycogenic precursors derived from other organs are used to maintain blood glucose levels. Glycerol and glycogenic amino acids derived from adipocytes and skeletal muscles are utilized as glycogenic precursors. Glycerol-3-phosphate dehydrogenase 1 (GPD1), an NAD(+)/NADH-dependent enzyme present in the cytosol, catalyzes the reversible conversion of glycerol-3-phosphate (G3P) to dihydroxyacetone phosphate (DHAP). Since G3P is one of the substrates utilized for gluconeogenesis in the liver, the conversion of G3P to DHAP by GPD1 is essential for maintaining blood glucose levels during fasting. We focused on GPD1 and examined its roles in gluconeogenesis during fasting.Methods. Using GPD1 null model BALB/cHeA mice (HeA mice), we measured gluconeogenesis from glycerol and the change of blood glucose levels under fasting conditions. We also measured gene expression related to gluconeogenesis in the liver and protein metabolism in skeletal muscle. BALB/cBy mice (By mice) were used as a control.Results. The blood glucose levels in the HeA mice were lower than that in the By mice after glycerol administration. Although lack of GPD1 inhibited gluconeogenesis from glycerol, blood glucose levels in the HeA mice after 1-4 h of fasting were significantly higher than that in the By mice. Muscle protein synthesis in HeA mice was significantly lower than that in the By mice. Moreover, blood alanine levels and usage of alanine for gluconeogenesis in the liver were significantly higher in the HeA mice than that in the By mice.Conclusions. Although these data indicate that a lack of GPD1 inhibits gluconeogenesis from glycerol, chronic GPD1 deficiency may induce an adaptation that enhances gluconeogenesis from glycogenic amino acids. (C) 2016 Elsevier Inc. All rights reserved.