Metabolic Regulation of PEPCK Isozymes

磷酸烯醇式丙酮酸羧酸激酶(PEPCK)是1953年由utter和Kurahashi等人发现的 50多年后，它的新陈代谢作用仍在解决。PEPCK是一种具有促发作用的酶，它 催化肝脏和肾脏糖异生的关键反应；然而，它存在于哺乳动物中 不产生葡萄糖的组织。PEPCK-C参与了一种称为甘油生成的途径，即 甘油三酯/脂肪酸循环的组成部分。这个循环是决定自由水平的一个主要因素 血液中的脂肪酸(FFA)，从而在胰岛素抵抗和2型糖尿病的发生中发挥作用 人类。在禁食期间，肥胖者体内的游离脂肪酸水平是循环中的三到四倍。大致 作为循环的一部分，脂肪分解释放的60%的游离脂肪酸被重新酯化为甘油三酯；这是 尤其重要的是肝脏，它有很高的FFA再酯化速度。3的主要来源是- 用于合成甘油三酯的磷酸甘油不是葡萄糖(通过糖酵解)，而是丙酮酸(通过 甘油生成)。甘油生成的决定酶是PEPCK-C，它也存在于 支持甘油三酯周转的肌肉。正如从它在甘油生成中的作用预测的那样， PEPCK-C在肌肉中的过度表达(PEPCK-CMUS小鼠)导致甘油三酯在 与肌肉中PEPCK-C的活性成正比的水平(甘油三酯可以超过 对照肌肉中的浓度)。PEPCK-CMU小鼠的摄食量是对照小鼠的两倍，但体重为20% 线粒体更少，线粒体更多。他们有非凡的剧烈运动的能力；未经训练的 PEPCK-CMUS小鼠可以以20m/min的跑步机速度连续跑步6k(未经训练的对照组 停在0.5米处)，使用储存的甘油三酯作为能源。尽管PEPCK-C对 肌肉新陈代谢和运动能力，几乎没有关于控制运动能力的因素的信息 特定肌肉类型中的PEPCK-C水平。在这项拨款申请中提出的研究旨在解决 关于PEPCK在哺乳动物中的作用的许多问题，其广泛的目标是将其功能联系起来 通过控制人类的甘油三酯/脂肪酸循环。

Phosphoenolpyruvate carboxykinase (PEPCK) was discovered in 1953 by Utter and Kurahashi, yet more than 50 years later its metabolic role is still being resolved. PEPCK is a cataplerotic enzyme, which catalyzes the key reaction in hepatic and renal gluconeogenesis; however, it is present in mammalian tissues that do not make glucose. PEPCK-C is involved in a pathway termed glyceroneogenesis, a component of the triglyceride/fatty acid cycle. This cycle is a major factor in determining the levels of free fatty acids (FFA) in the blood and thus plays a role the genesis of insulin resistance and Type 2 diabetes in humans. During fasting, obese humans have three to four times the level of circulating FFA. Approximately 60% of the FFA that is released by lipolysis is re-esterified to triglyceride as part of the cycle; this is especially important in the liver, which has a high rate of FFA re-esterification. The major source of the 3- phosphoglycerol used for triglyceride synthesis is not glucose (via glycolysis), but pyruvate (via glyceroneogenesis). The pace-setting enzyme in glyceroneogenesis is PEPCK-C, which also occurs in muscle where it supports the turnover of triglyceride. As predicted from its role in glyceroneogenesis, the over-expression of PEPCK-C in muscle (PEPCK-Cmus mice) results in an accumulation of triglyceride at a level that is proportional to the activity of PEPCK-C in the muscle (the triglyceride can exceed 10 times the concentration in control muscle). PEPCK-Cmus mice eat twice as much as control littermates, but weigh 20% less and have more mitochondria. They have an extraordinary capacity for strenuous exercise; untrained PEPCK-Cmus mice can run continuously for up to 6 k, at a treadmill speed of 20m/min (untrained controls stop at 0.5 m), using the stored triglyceride as an energy source. Despite the dramatic effect of PEPCK-C on muscle metabolism and exercise capacity, there is virtually no information about the factors that control the levels of PEPCK-C in specific muscle types. The research proposed in this grant application aims to resolve many of the issues concerning the role of PEPCK in mammals, with the broad goal of relating its function with the control of triglyceride/fatty acid cycling in humans.