Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism.
Phosphoenolpyruvate carboxykinase and the critical role of cataplerosis in the control of hepatic metabolism.
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DOI：
10.1186/1743-7075-2-33
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发表时间：
2005-11-21
影响因子：
4.5
通讯作者：
Hanson, Richard W
中科院分区：
文献类型：
--
作者：
Hakimi, Parvin;Johnson, Mark T;Hanson, Richard W
背景技术背景：PEPCK-C的代谢功能还不完全清楚;在小鼠中缺失该酶的基因提供了充分评估其功能的机会。方法：通过同源重组在小鼠中缺失磷酸烯醇丙酮酸羧激酶（GTP）（EC www.example.com）（PEPCK-C）的胞质形式的基因4.1.1.32结果：PEPCK-C-/-小鼠在出生后第二天变得严重低血糖，然后死于严重低血糖（12 mg/dl）。小鼠在出生后第二天胃中有牛奶，葡萄糖的施用提高了小鼠的血糖浓度，但没有导致存活率增加。出生后第二天，PEPCK-C-/-小鼠的肝脏甘油三酯含量是对照同窝小鼠的2 - 3倍。与对照动物相比，这些小鼠血液中的乳酸盐（2.5倍）、β-羟基丁酸盐（3倍）和甘油三酯（50%）也升高。出生后第2天，PEPCK-C-/-小鼠血液中丙氨酸、甘氨酸、谷氨酰胺、谷氨酸、天冬氨酸和天冬酰胺升高，血液尿素氮浓度增加2倍。两日龄PEPCK-C-/-小鼠肝切片将[2- 14 C]-乙酸盐和[5- 14 C]-谷氨酸盐氧化为14 CO2的速率大大降低，乙酸盐和葡萄糖合成脂肪酸的速率也大大降低。正如缺乏PEPCK-C所预测的那样，PEPCK-C-/-小鼠肝脏中的苹果酸浓度是对照组的10倍。我们的结论是，PEPCK-C不仅是必需的甘油生成和甘油生成，但也为cataplerosis（即柠檬酸循环阴离子的去除），并且该过程在PEPCK-C-/-小鼠导致柠檬酸循环流量显著减少，肝脂质分流为甘油三酯，导致脂肪肝。
BACKGROUND: The metabolic function of PEPCK-C is not fully understood; deletion of the gene for the enzyme in mice provides an opportunity to fully assess its function.METHODS: The gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) (EC 4.1.1.32) (PEPCK-C) was deleted in mice by homologous recombination (PEPCK-C-/- mice) and the metabolic consequences assessed.RESULTS: PEPCK-C-/- mice became severely hypoglycemic by day two after birth and then died with profound hypoglycemia (12 mg/dl). The mice had milk in their stomachs at day two after birth and the administration of glucose raised the concentration of blood glucose in the mice but did not result in an increased survival. PEPCK-C-/- mice have two to three times the hepatic triglyceride content as control littermates on the second day after birth. These mice also had an elevation of lactate (2.5 times), beta-hydroxybutyrate (3 times) and triglyceride (50%) in their blood, as compared to control animals. On day two after birth, alanine, glycine, glutamine, glutamate, aspartate and asparagine were elevated in the blood of the PEPCK-C-/- mice and the blood urea nitrogen concentration was increased by 2-fold. The rate of oxidation of [2-14C]-acetate, and [5-14C]-glutamate to 14CO2 by liver slices from PEPCK-C-/- mice at two days of age was greatly reduced, as was the rate of fatty acid synthesis from acetate and glucose. As predicted by the lack of PEPCK-C, the concentration of malate in the livers of the PEPCK-C-/- mice was 10 times that of controls.CONCLUSION: We conclude that PEPCK-C is required not only for gluconeogenesis and glyceroneogenesis but also for cataplerosis (i.e. the removal of citric acid cycle anions) and that the failure of this process in the livers of PEPCK-C-/- mice results in a marked reduction in citric acid cycle flux and the shunting of hepatic lipid into triglyceride, resulting in a fatty liver.