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.

磷酸烯醇丙酮酸羧基酶（PEPCK）在1953年被Utter和Kurahashi发现，但更多 比50年后，其代谢作用仍在解决。 PEPCK是一种催化酶，它是 催化肝和肾糖异生中的关键反应；但是，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，A 甘油三酸酯/脂肪酸周期的成分。该周期是确定自由水平的主要因素 血液中的脂肪酸（FFA），因此在胰岛素抵抗和2型糖尿病的起源中起作用 人类。在禁食期间，肥胖人类的循环FFA水平是三到四倍。大约 作为周期的一部分，通过脂解释放的FFA的60％被重新置于甘油三酸酯；这是 在肝脏中尤为重要，肝脏的重新固定速率很高。 3-的主要来源 用于甘油三酸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 甘油生成）。甘油发生中的速度定位酶是PEPCK-C，也发生在 肌肉支持甘油三酸酯的营业额。正如其在甘油发生中的作用所预测的那样 肌肉中PEPCK-C的过表达（PEPCK-CMUS小鼠）导致甘油三酸酯在A处积累 与PEPCK-C在肌肉中的活性成正比的水平（甘油三酸酯可能超过10倍的10倍 对照肌肉的浓度）。 pepck-cmus小鼠吃的食物是对照同窝仔的两倍，但重20％ 更少，有更多的线粒体。他们具有非凡的剧烈运动能力；未经训练 pepck-cmus小鼠可以以20m/min的跑步机速度连续运行高达6 k（未经训练的控件 使用储存的甘油三酸酯作为能源，停在0.5 m）。尽管PEPCK-C对 肌肉代谢和运动能力，几乎没有关于控制该因素的信息 特定肌肉类型中的PEPCK-C水平。本赠款申请中提出的研究旨在解决 关于PEPCK在哺乳动物中作用的许多问题，其功能的广泛目标 控制人类甘油三酸酯/脂肪酸循环。