Tucci Sara
Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, Medical Centre - University of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany.
J Inherit Metab Dis. 2017 May;40(3):317-323. doi: 10.1007/s10545-017-0016-8. Epub 2017 Feb 28.
Very-long-chain-acyl-CoA-dehydrogenase deficiency is the most common disorder of mitochondrial long-chain fatty acid (LCFA) oxidation, with an incidence of 1:50,000-1:100,000 in newborns. Catabolic situations contribute to the aggravation of symptoms and induce severe metabolic derangement. Treatment for VLCAD-deficiency includes avoidance of fasting and a long-chain fat-restricted and fat-modified diet in which LCFAs are fully or partially replaced by medium-chain triglycerides (MCT). The aim of this work was to investigate the outcome and the effects of long-term treatment in a mouse model of VLCAD-deficiency. The application of a single MCT bolus in a mouse model of VLCAD-deficiency (VLCAD mice) immediately prior to exercise protected the muscles from the accumulation of acylcarnitines providing the required energy and it did not affect hepatic lipid metabolism. However, when MCT was applied over the course of a year as a regular part of the diet, female VLCAD mice developed a severe clinical phenotype comparable to the human metabolic syndrome. Indeed, they were characterized by massive visceral fat infiltration, hepatosteatosis, disturbed fatty acid composition, hyperlipidemia, and systemic oxidative stress. In contrast, male VLCAD mice seemed to be protected and displayed only signs of insulin resistance. Besides the sex-specific response to MCT supplementation with regard to the lipid metabolism, all VLCAD mice developed progressive cardiac dysfunction over time which worsened when they were treated with regular MCT resulting in severe dilated cardiomyopathy. While long term use of MCT oil in mice has adverse effects, no such effects have been demonstrated in humans, likely reflecting the differences in long chain fatty acid oxidation between the two species.
极长链酰基辅酶A脱氢酶缺乏症是线粒体长链脂肪酸（LCFA）氧化最常见的疾病，在新生儿中的发病率为1:50,000 - 1:100,000。分解代谢情况会导致症状加重并引发严重的代谢紊乱。VLCAD缺乏症的治疗包括避免禁食以及采用长链脂肪限制和脂肪改良饮食，其中长链脂肪酸被中链甘油三酯（MCT）全部或部分替代。这项工作的目的是研究VLCAD缺乏症小鼠模型的长期治疗结果和效果。在运动前立即给VLCAD缺乏症小鼠模型（VLCAD小鼠）单次注射MCT可保护肌肉免受酰基肉碱积累的影响，提供所需能量，且不影响肝脏脂质代谢。然而，当MCT作为日常饮食的常规部分应用一年时，雌性VLCAD小鼠出现了与人类代谢综合征相当的严重临床表型。实际上，它们的特征是大量内脏脂肪浸润、肝脂肪变性、脂肪酸组成紊乱、高脂血症和全身氧化应激。相比之下，雄性VLCAD小鼠似乎受到了保护，仅表现出胰岛素抵抗的迹象。除了在脂质代谢方面对补充MCT有性别特异性反应外，所有VLCAD小鼠随着时间的推移都出现了进行性心脏功能障碍，当用常规MCT治疗时情况恶化，导致严重的扩张型心肌病。虽然在小鼠中长期使用MCT油有不良影响，但在人类中尚未证实有此类影响，这可能反映了两个物种在长链脂肪酸氧化方面的差异。
