Nutritional Treatment of Fat Oxidation Defect in Mice

描述（由申请人提供）：目前对遗传性脂肪酸氧化缺陷（FOD）患者的治疗包括为长链疾病提供大部分膳食脂肪作为中连链甘油三酯（主要是三辛酸），或对中、短链疾病提供简单的饮食脂肪限制。在许多情况下，这种治疗不能预防心脏、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（一种中等奇链甘油三酯）代替饮食中的三辛烷酸，可以迅速改善患者的临床状况和生活质量。我们假设，七酸酯和源自其初始肝脏代谢的c5酮体通过(i)提供丙酰辅酶a（柠檬酸循环（CAC）的一种复变底物）以及（ii）在通过一种或多种CAC酶的通量受到限制时补偿部分CAC阻断来发挥其有益作用。我们还假设奇链化合物，如三戊酸或c5酮体酯，可能对治疗中链FOD有用。最后，我们假设c5酮体β -羟基戊酸酯的三聚体可以作为β -羟基戊酸酯的缓慢肠内释放形式。

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.