Metabolic Regulation of PEPCK Isozymes

PEPCK 同工酶的代谢调节

• 批准号: 7212702
• 负责人: Richard W Hanson
• 金额: $ 33.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-08-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212702
• 关键词: Adipose tissue; Alanine; Animals; Applications Grants; Blood; Carbohydrates; Citric Acid Cycle; Condition; 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; Rate; Rattus; Reaction; Regulation; Research; Rest; Role; Running; Skeletal Muscle; Source; Speed; Strenuous Exercise; Striated Muscles; Time; Tissues; Triglycerides; in vivo; muscle metabolism

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：1953年由Utter和Kurahashi发现了磷酸烯醇丙酮酸羧酶（PEPCK），但50年后，其代谢作用仍在解决。 PEPCK是一种催化性酶，它催化肝和肾糖异生中的关键反应。但是，它存在于不产生葡萄糖的哺乳动物组织中。 PEPCK-C参与称为甘油生成的途径，这是甘油三酸酯/脂肪酸周期的成分。该循环是确定血液中游离脂肪酸（FFA）水平的主要因素，因此在人类中起作用胰岛素抵抗和2型糖尿病的起源。在禁食期间，肥胖人类的循环FFA水平是三到四倍。作为周期的一部分，将大约60％的FFA释放到甘油三酸酯中。这在肝脏中尤其重要，肝脏的重新固定速率很高。用于甘油三酸酯合成的3-磷酸甘油的主要来源不是葡萄糖（通过糖酵解），而是丙酮酸（通过甘油生成）。甘油生成中的速度定位酶是PEPCK-C，它也发生在支持甘油三酸酯营业额的肌肉中。正如其在甘油生成中的作用所预测的那样，肌肉中PEPCK-C（PEPCK-CMUS小鼠）的过度表达导致甘油三酸酯在与肌肉中PEPCK-C活性成正比的水平上积累（甘油三酸酯在对照肌肉中的浓度可以超过10倍）。 pepck-cmus小鼠吃的食物是对照同窝仔的两倍，但重20％，线粒体更多。他们具有非凡的剧烈运动能力；未经训练的PEPCK-CMU小鼠可以使用存储的甘油三酸酯作为能源，以20m/min的跑步机速度（未经训练的对照在0.5 m处停止）可以连续运行至6 K。尽管PEPCK-C对肌肉代谢和运动能力产生了巨大影响，但几乎没有关于控制特定肌肉类型中PEPCK-C水平的因素的信息。该赠款应用程序中提出的研究旨在解决有关PEPCK在哺乳动物中作用的许多问题，其广泛的目标是将其功能与控制人类的甘油三酸酯/脂肪酸循环的控制联系起来。