Metabolic Regulation of PEPCK Isozymes

PEPCK 同工酶的代谢调节

• 批准号: 7864647
• 负责人: Richard W Hanson
• 金额: $ 1.88万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7864647
• 关键词: Adipose tissue; Alanine; Animals; Applications Grants; Blood; Carbohydrates; Citric Acid Cycle; Diet; Eating; Energy Metabolism; Energy-Generating Resources; Enzymes; Epinephrine; Esterification; Exercise; Fasting; Fatty Acids; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Glucocorticoids; Gluconeogenesis; Glucose; Glycogen; Glycolysis; Goals; Hepatic; Hormones; Human; Hypertriglyceridemia; Indium; Insulin Resistance; Isoenzymes; Kidney; Lipolysis; Liver; Mammals; Measures; Messenger RNA; Metabolic; Metabolism; Methods; Mitochondria; Modeling; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Pathway interactions; Performance; Phosphoenolpyruvate Carboxylase; Physiological; Play; Process; Pyruvate; Pyruvates; Rattus; Reaction; Regulation; Research; Rest; Role; Running; Skeletal Muscle; Source; Speed; Strenuous Exercise; Striated Muscles; Time; Tissues; Triglycerides; in vivo; muscle metabolism

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.

磷酸烯醇式丙酮酸羧激酶（PEPCK）是由Utter和Kurahashi于1953年发现的， 50多年后，它的代谢作用仍在研究中。PEPCK是一种分解酶， 催化肝和肾再生中的关键反应;然而，它存在于哺乳动物中， 不产生葡萄糖的组织。PEPCK-C参与称为甘油生成的途径， 甘油三酯/脂肪酸循环的组成部分。这一周期是决定免费水平的主要因素。 脂肪酸（FFA）在血液中，因此发挥作用的胰岛素抵抗和2型糖尿病的起源， 人类在禁食期间，肥胖人群的循环FFA水平是正常人的三到四倍。约 作为循环的一部分，由脂解释放的60%的FFA被重新酯化为甘油三酯;这是 在肝脏中尤其重要，肝脏具有高FFA再酯化率。3的主要来源- 用于甘油三酯合成的磷酸甘油不是葡萄糖（通过糖酵解），而是丙酮酸（通过糖酵解）。 甘油生成）。甘油生成中的起搏酶是PEPCK-C，它也发生在 支持甘油三酯周转的肌肉。正如从其在甘油生成中的作用所预测的， PEPCK-C在肌肉中的过度表达（PEPCK-Cmus小鼠）导致甘油三酯以 与肌肉中PEPCK-C的活性成比例的水平（甘油三酯可以超过肌肉中PEPCK-C的10倍）。 对照肌肉中的浓度）。PEPCK-Cmus小鼠的食量是对照组的两倍，但体重是对照组的20%。 少而线粒体多。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20米/分钟的跑步机速度连续跑6公里（未经训练的对照组 在0.5 m处停止），使用储存的甘油三酯作为能量源。尽管PEPCK-C对 肌肉代谢和运动能力，几乎没有关于控制肌肉代谢的因素的信息。 PEPCK-C在特定肌肉类型中的水平。这项研究的目的是解决 许多关于PEPCK在哺乳动物中作用的问题，其广泛目标是将其功能 控制人体甘油三酯/脂肪酸循环。