Metabolic Regulation of PEPCK Isozymes

人体糖脂代谢的相互作用是维持正常能量平衡的关键。长期以来，人们一直知道糖尿病涉及脂代谢障碍，这种损害以一种模糊的方式导致了疾病的并发症。J.Denis McGary在一篇题为如果Minkowski是Ageusic会怎么样的文章中写道。关于糖尿病的另一种视角，(1)建议对糖尿病的传统研究有错误的侧重点，如果从脂代谢异常的背景来看，胰岛素抵抗和高血糖可能是最好的理解。脂肪组织中脂肪酸再酯化速率的降低可能是调节脂肪酸向肝脏输送的一个关键因素。1968年，我们首次描述了脂肪组织中脂肪酸的再酯化途径，称为甘油生成，随后被证明是脂肪组织和肝脏合成甘油三酯所需的3-甘油磷酸的重要因素。这一途径可能在控制脂肪组织和肝脏中甘油三酯的合成以及控制饥饿时脂肪组织中的脂肪酸流量方面发挥重要作用。在这一途径中，大鼠控制步骤PEPCK的基因的组织特异性表达已经在小鼠身上被消融，导致脂肪肝的发展和正常生长的缺乏。在这项拨款申请中描述的研究将探索哺乳动物组织中甘油生成的生理学意义，并通过控制向肝脏输送游离脂肪酸的速率来确定PEPCK在糖尿病调节中的作用。此外，将使用转基因小鼠来确定PEPCK在肾脏、小肠、脑、骨骼肌和棕色脂肪组织中的作用。

The interaction of glucose and lipid metabolism in humans is critical for maintaining normal energy balance. Diabetes has long been known to involve impairment in lipid metabolism that contributes in an ill-defined manner to the complications of the disease. J. Denis McGary, in a provocative article entitled What if Minkowski had been Ageusic? An Alternative Angle on Diabetes, (1) suggested traditional research on diabetes had the wrong emphasis and that insulin resistance and hyperglycemia might best be understood if viewed from the context of an abnormality on lipid metabolism. A decreased rate of fatty acid re-esterfication by adipose tissue could be a critical factor in regulating the delivery of fatty acids to the liver. In 1968, we first described a pathway for the re- esterfication of fatty acids in adipose tissue, termed glyceroneogenesis, that has subsequently been shown to be a significant factor in the generation of 3-glycerolphosphate required for triglyceride synthesis in both adipose tissue and liver. This pathway may play an important role in the control of triglyceride synthesis in adipose tissue and liver and control the flux of fatty acids from adipose tissue during starvation. The tissue-specific expression of the gene for the rat controlling step in this pathway, PEPCK, has been ablated in mice causing the development of fatty liver and a lack of normal growth. The research described in this grant application will explore the physiological significance of glyceroneogenesis in mammalian tissues and establish the role of PEPCK in the regulation of diabetes by controlling the rate of free fatty acid delivery to the liver. In addition, the role of PEPCK in tissue such as kidney, small intestine, brain, skeletal muscle and brown adipose tissue will be determined using genetically modified mice.