Nutritional Treatment of Fat Oxidation Defect in Mice

描述（由申请人提供）：目前遗传性脂肪酸氧化缺陷（FOD）患者的治疗包括提供大部分膳食脂肪，如长链疾病的中偶链甘油三酯（主要是三辛酸甘油酯）或中链和短链疾病的简单膳食脂肪限制。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。一项初步临床试验表明，用三庚酸甘油酯（一种中等奇数链甘油三酯）取代饮食中的三辛酸甘油酯，可迅速改善患者的临床状况和生活质量。我们假设庚酸及其初始肝脏代谢产生的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）当通过一种或多种CAC酶的通量受到限制时，补偿部分CAC阻断。我们还假设，奇数链化合物，如三戊酸甘油酯或酯的C5-酮体可能是有用的治疗中链FOD。最后，我们假设C5-酮体β-羟基戊酸酯的三聚体可以用作β-羟基戊酸酯的缓慢肠内释放形式。 我们提出了一个研究计划，在小鼠中进行非常长链酰基辅酶A脱氢酶（VLCAD，目的1 - 4）和线粒体三功能蛋白（MTP，目的5）缺陷。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。这将使用在其丙酰基或乙酰基部分中标记有13 C的化合物来实现，以通过质量同位素异构体分析分别评价回补和氧化。 2.为了测试奇数链化合物是否（i）改善通过禁食或/和冷暴露应激的敲除小鼠的存活，和（ii）改善在应激诱导的条件（高工作负荷或肾上腺素能刺激）下心脏和肌肉的能量代谢和机械性能。 3.为了测试急性治疗FOD失代偿的新途径，即，奇数链回补底物（三庚酸甘油酯、三戊酸甘油酯、甘油β-酮戊酸酯）的肠胃外制剂。为了测试β-羟基戊酸酯（triethyl）的环状三聚体作为丙酰-CoA前体的缓慢肠溶释放形式的实用性，其适用于患者的夜间覆盖。提高新生MTP -/-小鼠的存活率。

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.