Group on Molecular and Cell Biology of Lipids, the Alberta Diabetes Institute, the Mazankowski Alberta Heart Institute, Edmonton, Alberta, CanadaDepartment of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.
Group on Molecular and Cell Biology of Lipids, the Alberta Diabetes Institute, the Mazankowski Alberta Heart Institute, Edmonton, Alberta, CanadaDepartment of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada.
Diabetes. 2014 Aug;63(8):2620-30. doi: 10.2337/db13-0993. Epub 2014 Mar 27.
Phosphatidylethanolamine (PE) N-methyltransferase (PEMT) catalyzes the synthesis of phosphatidylcholine (PC) in the liver. Mice lacking PEMT are protected against diet-induced obesity and insulin resistance. We investigated the role of PEMT in hepatic carbohydrate metabolism in chow-fed mice. A pyruvate tolerance test revealed that PEMT deficiency greatly attenuated gluconeogenesis. The reduction in glucose production was specific for pyruvate; glucose production from glycerol was unaffected. Mitochondrial PC levels were lower and PE levels were higher in livers from Pemt(-/-) compared with Pemt(+/+) mice, resulting in a 33% reduction of the PC-to-PE ratio. Mitochondria from Pemt(-/-) mice were also smaller and more elongated. Activities of cytochrome c oxidase and succinate reductase were increased in mitochondria of Pemt(-/-) mice. Accordingly, ATP levels in hepatocytes from Pemt(-/-) mice were double that in Pemt(+/+) hepatocytes. We observed a strong correlation between mitochondrial PC-to-PE ratio and cellular ATP levels in hepatoma cells that expressed various amounts of PEMT. Moreover, mitochondrial respiration was increased in cells lacking PEMT. In the absence of PEMT, changes in mitochondrial phospholipids caused a shift of pyruvate toward decarboxylation and energy production away from the carboxylation pathway that leads to glucose production.
磷脂酰乙醇胺 N-甲基转移酶（PEMT）催化肝脏中磷脂酰胆碱（PC）的合成。缺乏 PEMT 的小鼠可以预防饮食诱导的肥胖和胰岛素抵抗。我们研究了 PEMT 在正常饮食喂养的小鼠肝内碳水化合物代谢中的作用。丙酮酸耐量试验表明，PEMT 缺乏极大地减弱了糖异生。葡萄糖生成对丙酮酸的减少是特异的；甘油的葡萄糖生成不受影响。与 Pemt(+/+)小鼠相比，Pemt(-/-)小鼠肝脏中的线粒体 PC 水平较低，PE 水平较高，导致 PC 与 PE 的比值降低 33%。Pemt(-/-)小鼠的线粒体也更小且更长。Pemt(-/-)小鼠线粒体中的细胞色素 c 氧化酶和琥珀酸还原酶活性增加。因此，Pemt(-/-)小鼠肝细胞中的 ATP 水平是 Pemt(+/+)肝细胞的两倍。我们观察到在表达不同量 PEMT 的肝癌细胞中，线粒体 PC 与 PE 的比值与细胞内 ATP 水平之间存在很强的相关性。此外，缺乏 PEMT 会增加线粒体呼吸。在缺乏 PEMT 的情况下，线粒体磷脂的变化导致丙酮酸向脱羧和能量产生转移，而不是向导致葡萄糖生成的羧化途径转移。
