Metabolic Regulation of PEPCK Isozymes

PEPCK 同工酶的代谢调节

• 批准号: 6364669
• 负责人: Richard W Hanson
• 金额: $ 37.05万
• 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 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6364669
• 关键词: adipose tissue; biological models; blood chemistry; diabetes mellitus; esterification; fatty acid metabolism; fatty acids; gene expression; gene targeting; genetically modified animals; glucose; glucose metabolism; glycerol; growth /development; laboratory mouse; liver; molecular pathology; nutrition related tag; phosphoenolpyruvate carboxylase; polymerase chain reaction; protein localization; protein structure function; radiotracer; small intestines; starvation; triglycerides

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.

人体中葡萄糖和脂质代谢的相互作用对于维持正常的能量平衡至关重要。长期以来，人们都知道糖尿病涉及脂质代谢的损害，而脂质代谢的损害以不明确的方式促成了糖尿病的并发症。 J. Denis McGary在一篇题为《如果闵可夫斯基是音乐家会怎么样？》（What if Minkowski had been Musical？ 糖尿病的另一个角度，（1）建议传统的糖尿病研究有错误的重点，如果从脂质代谢异常的背景下，胰岛素抵抗和高血糖症可能是最好的理解。 脂肪组织的脂肪酸再酯化率降低可能是调节脂肪酸向肝脏输送的关键因素。 在1968年，我们首先描述了脂肪组织中脂肪酸再酯化的途径，称为甘油生成，随后已显示其是脂肪组织和肝脏中甘油三酯合成所需的3-甘油磷酸的产生的重要因素。 该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期间脂肪组织中脂肪酸的通量中起重要作用。该途径中大鼠控制步骤的基因PEPCK的组织特异性表达已在小鼠中被消除，导致脂肪肝的发展和缺乏正常生长。 这项研究将探索哺乳动物组织中甘油生成的生理意义，并通过控制游离脂肪酸输送到肝脏的速率来确定PEPCK在糖尿病调节中的作用。 此外，PEPCK在组织如肾脏、小肠、脑、骨骼肌和棕色脂肪组织中的作用将使用遗传修饰的小鼠来确定。