Overexpression of glutamine: fructose-6-phosphate amidotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance.
Overexpression of glutamine: fructose-6-phosphate amidotransferase in the liver of transgenic mice results in enhanced glycogen storage, hyperlipidemia, obesity, and impaired glucose tolerance.
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DOI：
10.2337/diabetes.49.12.2070
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发表时间：
2000-12
期刊：
影响因子：
7.7
通讯作者：
G. Veerababu;Jiping Tang;Rosemary T. Hoffman;Marc C. Daniels;L. F. Hebert;E. Crook;R. Cooksey;Donald A. McClain
中科院分区：
文献类型：
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作者：
G. Veerababu;Jiping Tang;Rosemary T. Hoffman;Marc C. Daniels;L. F. Hebert;E. Crook;R. Cooksey;Donald A. McClain
为了检查肝脏中己糖胺通量增加的影响，使用PEPCK启动子在转基因小鼠中过表达己糖胺生物合成中的限速酶（谷氨酰胺：果糖-6-磷酸酰胺转移酶[GFA]）。随机喂养的转基因小鼠肝脏的GFA活性是非转基因对照组小鼠的1.6倍（转基因小鼠为276 +/- 24 pmol x mg（-1）x min（-1），对照组为176 +/- 18 pmol x mg（-1）x min（-1），P < 0.05）和较高水平的己糖胺终产物UDP-N-乙酰葡糖胺（转基因小鼠中288 +/- 11 pmol/g对对照中233 +/- 10 pmol/g，P < 0.001）。与对照组小鼠相比，年龄较小的转基因小鼠空腹血糖较低（转基因小鼠为4.8 +/- 0.5 mmol/l，对照组为6.5 +/- 0.8 mmol/l，P < 0.05），胰岛素水平不高（转基因小鼠为48.0 +/- 7.8 pmol/l，对照组为56.4 +/- 5.4 pmol/l，P = NS）;转基因雄性动物的胰岛素水平显著较低（P < 0.05）。在6个月大时，通过高胰岛素钳夹技术，转基因动物具有正常的胰岛素敏感性。转基因小鼠的肝糖原含量较高（转基因小鼠为108.6 +/- 5.2 pmol/g，对照组为32.8 +/- 1.3 micromol/g，P < 0.01），与糖原合酶的不适当激活有关。游离脂肪酸（FFA）和甘油三酯的血清水平也升高（FFA，转基因小鼠为0.67 +/- 0.03 mmol/l，对照组为0.14 +/- 0.01;甘油三酯，转基因小鼠为1.34 +/- 0.15 mmol/l，对照组为0.38 +/- 0.01，P < 0.01）。年龄较大的转基因小鼠变得比对照小鼠重，并表现出相对的葡萄糖耐受不良和胰岛素抵抗。转基因小鼠8月龄时的葡萄糖代谢率为154 +/- 5 mg x kg（-1）x min（-1），对照组为191 +/- 6 mg x kg（-1）x min（-1）（P < 0.05）。我们的结论是，己糖胺是介导的葡萄糖敏感的调节肝糖原和脂质代谢。肝脏中氨基己糖流量的增加标志着向燃料储存的转变，最终导致肥胖和胰岛素抵抗。
To examine the effect of increased hexosamine flux in liver, the rate-limiting enzyme in hexosamine biosynthesis (glutamine:fructose-6-phosphate amidotransferase [GFA]) was overexpressed in transgenic mice using the PEPCK promoter. Liver from random-fed transgenic mice had 1.6-fold higher GFA activity compared with nontransgenic control littermates (276 +/- 24 pmol x mg(-1) x min(-1) in transgenic mice vs. 176 +/- 18 pmol x mg(-1) x min(-1) in controls, P < 0.05) and higher levels of the hexosamine end product UDP-N-acetyl glucosamine (288 +/- 11 pmol/g in transgenic mice vs. 233 +/- 10 pmol/g in controls, P < 0.001). Younger transgenic mice compared with control mice had lower fasting serum glucose (4.8 +/- 0.5 mmol/l in transgenic mice vs. 6.5 +/- 0.8 mmol/l in controls, P < 0.05) without higher insulin levels (48.0 +/- 7.8 pmol/l in transgenic mice vs. 56.4 +/- 5.4 pmol/l in controls, P = NS); insulin levels were significantly lower in transgenic males (P < 0.05). At 6 months of age, transgenic animals had normal insulin sensitivity by the hyperinsulinemic clamp technique. Hepatic glycogen content was higher in the transgenic mice (108.6 +/- 5.2 pmol/g in transgenic mice vs. 32.8 +/- 1.3 micromol/g in controls, P < 0.01), associated with an inappropriate activation of glycogen synthase. Serum levels of free fatty acids (FFAs) and triglycerides were also elevated (FFAs, 0.67 +/- 0.03 mmol/l in transgenic mice vs. 0.14 +/- 0.01 in controls; triglycerides, 1.34 +/- 0.15 mmol/l in transgenic mice vs. 0.38 +/- 0.01 in controls, P < 0.01). Older transgenic mice became heavier than control mice and exhibited relative glucose intolerance and insulin resistance. The glucose disposal rate at 8 months of age was 154 +/- 5 mg x kg(-1) x min(-1) in transgenic mice vs. 191 +/- 6 mg x kg(-1) x min(-1) in controls (P < 0.05). We conclude that hexosamines are mediators of glucose sensing for the regulation of hepatic glycogen and lipid metabolism. Increased hexosamine flux in the liver signals a shift toward fuel storage, resulting ultimately in obesity and insulin resistance.