Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Centre, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany.
Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany.
Nutrients. 2023 Nov 5;15(21):4689. doi: 10.3390/nu15214689.
Defects in mitochondrial fatty acid β-oxidation (FAO) impair metabolic flexibility, which is an essential process for energy homeostasis. Very-long-chain acyl-CoA dehydrogenase (VLCADD; OMIM 609575) deficiency is the most common long-chain mitochondrial FAO disorder presenting with hypoglycemia as a common clinical manifestation. To prevent hypoglycemia, triheptanoin-a triglyceride composed of three heptanoates (C7) esterified with a glycerol backbone-can be used as a dietary treatment, since it is metabolized into precursors for gluconeogenesis. However, studies investigating the effect of triheptanoin on glucose homeostasis are limited. To understand the role of gluconeogenesis in the pathophysiology of long-chain mitochondrial FAO defects, we injected VLCAD-deficient (VLCAD) mice with C-glycerol in the presence and absence of heptanoate (C7). The incorporation of C-glycerol into blood glucose was higher in VLCAD mice than in WT mice, whereas the difference disappeared in the presence of C7. The result correlates with C enrichment of liver metabolites in VLCAD mice. In contrast, the C7 bolus significantly decreased the C enrichment. These data suggest that the increased contribution of gluconeogenesis to the overall glucose production in VLCAD mice increases the need for gluconeogenesis substrate, thereby avoiding hypoglycemia. Heptanoate is a suitable substrate to induce glucose production in mitochondrial FAO defect.
线粒体脂肪酸β-氧化（FAO）缺陷会损害代谢灵活性，这是能量平衡的一个重要过程。长链酰基辅酶 A 脱氢酶（VLCADD；OMIM 609575）缺乏症是最常见的长链线粒体 FAO 紊乱，其表现为低血糖，这是常见的临床表现。为了防止低血糖，可以使用三庚酸酯（由三个庚酸酯（C7）与甘油主链酯化而成的三甘油酯）作为饮食治疗，因为它可以代谢为糖异生的前体。然而，关于三庚酸酯对葡萄糖稳态影响的研究有限。为了了解糖异生在长链线粒体 FAO 缺陷病理生理学中的作用，我们在存在和不存在庚酸（C7）的情况下向 VLCAD 缺陷（VLCAD）小鼠注射 C-甘油。与 WT 小鼠相比，C-甘油掺入血糖中的比例在 VLCAD 小鼠中更高，而在存在 C7 的情况下，这种差异消失了。结果与 VLCAD 小鼠肝脏代谢物的 C 富集相关。相比之下，C7 弹丸显著降低了 C 富集。这些数据表明，VLCAD 小鼠中糖异生对总体葡萄糖生成的贡献增加，增加了对糖异生底物的需求，从而避免了低血糖。庚酸是诱导线粒体 FAO 缺陷中葡萄糖生成的合适底物。
