Nutritional Treatment of Fat Oxidation Defect in Mice

描述(申请人提供)：目前对遗传性脂肪酸氧化缺陷(FOD)患者的治疗包括提供大部分饮食脂肪作为中偶链甘油三酯(主要是三辛酸)，用于长链疾病，或简单地限制饮食脂肪，用于中、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。一项初步的临床试验表明，用一种中等单链甘油三酯--三庚烷取代饮食中的三辛酸，可以迅速改善患者的临床状况和生活质量。我们假设，庚酸和源于其初始肝脏代谢的C5-酮体，通过(I)提供柠檬酸循环(CAC)的抗酸底物丙酸I-CoA，以及(Ii)当通过一个或多个CAC酶的通量受到限制时，补偿部分CAC阻断，从而发挥其有益的作用。我们还假设，奇链化合物，如三碳五环或C5-酮体的酯，可能在治疗中链FOD方面有用。最后，我们假设C5-酮体的三聚体β-羟基戊酸可以用作β-羟基戊酸的缓释形式。 我们建议在缺乏超长链乙酰辅酶A脱氢酶(VLCAD，AIMS 1-4)和线粒体三功能蛋白(MTP，AIM 5)的小鼠中进行研究。我们的具体目标是： 表征单链化合物在体内和灌流器官(心脏、肌肉和肝脏)中的代谢和代谢作用。这将使用在其丙酰基或乙酰基部分标记有13C的化合物来实现，以通过质量同位素分析分别评估失活和氧化。 2.检测奇链化合物(I)是否改善禁食或/和冷暴露应激基因敲除小鼠的存活，以及(Ii)改善应激诱导条件(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.探索FOD失代偿急性治疗的新途径，即单链抗炎底物(三庚酸、三戊酸甘油、β-酮戊酸甘油)的肠外制剂。测试β-羟基戊酸酯的环状三聚体(Triolide)作为丙酰辅酶A前体的一种缓释形式的实用性，适用于夜间覆盖患者。以提高新生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.