CARBOHYDRATE AND LIPID METABOLIC PATHWAYS

碳水化合物和脂质代谢途径

• 批准号: 3483061
• 负责人: BERNARD R LANDAU
• 金额: $ 29.5万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-05-01 至 1993-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3483061
• 关键词: Krebs' cycle; NAD(H) phosphate; acetaminophen; acetone; acetyl coA; alpha ketoglutarate; carbohydrate metabolism; cholesterol; diabetes mellitus; fructose; galactose; glucagon; gluconeogenesis; glucose 6 phosphatase; glucuronides; glutamine; high performance liquid chromatography; human subject; laboratory rat; lipid metabolism; liver metabolism; mannose; noninsulin dependent diabetes mellitus; oxidation; perfusion; phenylacetates; radiotracer; steroid biosynthesis; tritium

Methods are to be developed and applied for quantitating pathways in physiological and pathological states with three specific aims. First, methods are to be developed for noninvasively sampling in humans intermediates of carbohydrate metabolism: a) The use of 13C rather than 14C to sample hepatic glucose-6-P with acetaminophen glucuronide will be examined and whether the glucuronide sample a single pool of hepatic glucose- 6-P and UDP-glucose will be further assessed by (1) administering various labeled substrates to normal subjects and comparing 14C distributions in glucuronide and blood glucose and (2) comparing distributions in glucuronide and glycogen from rats given 14C glucose and acetaminophen; b) Phenylacetate will be given to normals with 14C substrates to see if its urinary glutamine conjugate reflects hepatic alpha-ketoglutarate; c) Similary, it will be determine if the glycine conjugate of benzoic acid reflects hepatic 3-phosphoglyceric acid. Second, in part using these probes where applicable: a) The extent of futile cycling in normals, type II diabetics and thyrotoxics will be estimated correcting for (1) the extent of retention of 3H from (2- 3h)glucose-6-P, (2) the detritiation of (3-3H)glucose in the pentose cycle and (3) the retention of 3H of (6-3H)glucose in Cori cycling; b) The extent of isotopic equilibration of hepatic glucose-6-P with fructose-6-P and the pentose-5-P's will be estimated and the data applied to a model for quantitating pentose cycle activity in liver; c) The contribution of the indirect pathway in the fed state will be estimated from randomization of 14C from (6-14C)glucose, the site of the pathway assessed from comparisons of randomizations from 14C galactose, mannose, and the phenylacetate probe used to estimate 12C dilution of 14C in the Krebs cycle; d) If possible, the phenylacetate probe will also be to quantitate the pathways of acetaone metabolism. Third, by specifically labeling the acetyl CoA formed in the cellular evnironment of omega-oxidation and the peroxisomes and of NADPH formed in the endoplasmic reticulum in the rat, determine if there are specific pools of acetyl and NADPH used for cholesterol synthesis in liver.

要开发和应用定量的方法 生理和病理状态的通路有三个 明确的目标。首先，要制定方法，以 人体内碳水化合物中间体的非侵入性取样 新陈代谢：a)使用13C而不是14C对肝脏进行采样 将检测含有对乙酰氨基酚葡萄糖醛酸苷的葡萄糖-6-P和 不管葡萄糖醛酸苷是不是只采集了一池肝脏葡萄糖- 6-P和UDP-葡萄糖将通过(1)注射进一步评估 不同标记底物与正常人~(14)C的比较 葡萄糖醛酸苷和血糖的分布及(2)比较 ~(14)C染毒大鼠体内葡萄糖醛酸和糖原的分布 葡萄糖和对乙酰氨基酚；b)苯乙酸酯 用14C底物检测正常人尿谷氨酰胺 结合物反映肝脏α-酮戊二酸；c)类似，它将 正在测定苯甲酸的甘氨酸结合物是否反映 肝脏3-磷酸甘油酸。第二，在一定程度上使用这些 在适用的情况下进行探测：a)徒劳的自行车在 将估计正常人、II型糖尿病患者和甲状腺功能亢进症患者 修正(1)~(2-)中的~3H的保留范围 ~3H)葡萄糖-6-P，(2)戊糖中(3-~H)葡萄糖的损伤 (3)CORI循环中~(6-H)葡萄糖的~3H滞留； B)肝脏葡萄糖-6-P的同位素平衡程度 果糖-6-P和戊糖-5-P将被估计和数据 应用于量化肝脏中戊糖循环活性的模型； C)美联储状态中的间接途径的贡献将 从(6-14C)葡萄糖的14C随机化估计， 通过随机化比较评估路径的位置 从14C半乳糖、甘露糖和苯乙酸酯探针中 估计克雷布斯循环中14C的12C稀释；d)如果可能， 苯乙酸乙酯探针也将用于定量检测 丙酮代谢。第三，通过特别标记乙酰 在omega-氧化和细胞环境中形成CoA 内质中形成的过氧化物体和NADPH 在大鼠的网状结构中，确定是否有特定的池 乙酰和NADPH用于肝脏中胆固醇的合成。