Nutritional Treatment of Fat Oxidation Defect in Mice

小鼠脂肪氧化缺陷的营养治疗

• 批准号: 7069174
• 负责人: Henri Brunengraber
• 金额: $ 39.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7069174
• 关键词: Krebs' cycle; acyl coA dehydrogenases; bioenergetics; carnitine palmitoyltransferase 1; chemical structure; diet therapy; dietary lipid; enzyme deficiency; fatty acids; gas chromatography mass spectrometry; genetically modified animals; heart metabolism; isovaleric acidemia; laboratory mouse; lipid metabolism; liquid chromatography mass spectrometry; liver metabolism; long chain fatty acid; metabolism disorder; muscle metabolism; nutrition related tag; oxidation; short chain fatty acid

DESCRIPTION (provided by applicant): The current treatment of patients with inherited fatty acid oxidation defects (FOD) involves providing most of the dietary fat as medium even-chain triglycerides (mostly trioctanoin) for long-chain disorders or simply dietary fat restriction for medium- and short chain disorders. This treatment does not prevent, in many cases, the progressive deterioration of cardiac, muscular, and/or retinal function. An initial clinical trial has shown that replacing trioctanoin in the diet by triheptanoin, a medium odd-chain triglyceride, leads to a rapid improvement of the patients' clinical condition and quality of life. We hypothesize that heptanoate, and the C5-ketone bodies derived from its initial hepatic metabolism, exert their beneficial effects by (i) providing propionyI-CoA, an anaplerotic substrate for the citric acid cycle (CAC), and (ii) compensating for partial CAC blockade when the flux through one or more CAC enzymes is restricted. We also hypothesize that odd-chain compounds such as tripentanoin or esters of C5-ketone bodies could be useful in the treatment of medium-chain FOD. Lastly, we hypothesize that a trimer of the C5-ketone body beta-hydroxypentanoate could be used as a slow enteral release form of beta-hydroxypentanoate. We propose a research program to be conducted in mice deficient in very long-chain acyI-CoA dehydrogenase (VLCAD, Aims 1 -4) and in mitochondrial trifunctional protein (MTP, Aim 5). Our specific aims are: To characterize the metabolism and metabolic effects of the odd-chain compounds in vivo and in perfused organs (heart, muscle and liver). This will be achieved using compounds labeled with 13C in their propionyl or acetyl moiety, to evaluate anaplerosis and oxidation, respectively, by mass isotopomer analysis. 2. To test whether the odd-chain compounds (i) improve the survival of knock-out mice stressed by fasting or/and cold exposure, and (ii) improve energy metabolism and mechanical performance of the heart and muscle under stress-induced conditions (high workload or adrenergic stimulation). 3. To test new avenues for the acute treatment of FOD decompensation, i.e., parenteral preparations of odd-chain anaplerotic substrates (triheptanoin, tripentanoin, glycerol beta-ketopentanoate). To test the practicality of the cyclical trimer of beta-hydroxypentanoate (triolide) as a slow enteric release form of the propionyl-CoA precursor, suitable for nocturnal coverage of patients. To improve the survival of newborn MTP -/- mice.

描述（由申请人提供）：目前对患有遗传性脂肪酸氧化缺陷（FOD）的患者的治疗包括提供大部分膳食脂肪作为中等偶数链甘油三酯（主要是三辛酸甘油酯）以治疗长链疾病或简单地限制膳食脂肪以治疗中等偶数链甘油三酯（主要是三辛酸甘油酯）。 - 和短链疾病。在许多情况下，这种治疗不能防止心脏、肌肉和/或视网膜功能的进行性恶化。初步临床试验表明，用三庚酸甘油酯（一种中等奇链甘油三酯）替代饮食中的三辛酸可以快速改善患者的临床状况和生活质量。我们假设庚酸和源自其最初肝脏代谢的 C5 酮体通过以下方式发挥其有益作用：(i) 提供丙酰辅酶 A，柠檬酸循环 (CAC) 的回补底物，以及 (ii) 补偿部分当通过一种或多种 CAC 酶的通量受到限制时，CAC 阻断。我们还假设奇数链化合物如三戊酸或 C5-酮体酯可用于治疗中链 FOD。最后，我们假设 C5-酮体 β-羟基戊酸的三聚体可以用作 β-羟基戊酸的缓慢肠内释放形式。 我们提议在缺乏极长链酰基辅酶A脱氢酶（VLCAD，目标1 -4）和线粒体三功能蛋白（MTP，目标5）的小鼠中进行一项研究计划。我们的具体目标是： 表征奇数链化合物在体内和灌注器官（心脏、肌肉和肝脏）中的代谢和代谢效应。这将通过使用丙酰基或乙酰基部分用 13C 标记的化合物来实现，通过质量同位素分析分别评估回补和氧化。 2. 测试奇数链化合物是否（i）提高因禁食或/和寒冷暴露而应激的基因敲除小鼠的存活率，以及（ii）改善应激条件下心脏和肌肉的能量代谢和机械性能（高工作负荷或肾上腺素刺激）。 3. 测试急性FOD失代偿治疗的新途径，即奇数链回补底物（三庚酸甘油酯、三戊酸甘油酯、甘油β-酮戊酸）的肠胃外制剂。测试β-羟基戊酸（三内酯）环状三聚体作为丙酰辅酶A前体的缓慢肠溶释放形式的实用性，适合患者夜间使用。提高新生MTP -/- 小鼠的存活率。