Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Abstract

This article is available online at http://www.jlr.org symptoms include i) severe energy deficiency due to a deficient fatty acid oxidation and subsequent impairment of ketone body biosynthesis and ii) accumulation of toxic long-chain acylcarnitines. Therefore, catabolic situations in which the organism mainly relies on fatty acid oxidation induce symptoms and severe metabolic derangement. The clinical phenotype is very heterogeneous and presents with different severity and age of onset (3), involving organs and tissues that mostly rely on fatty acid -oxidation for energy production. To date, treatment recommendations (5) include a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids are fully or in part replaced by medium-chain triglycerides (MCTs) (1, 5) and the avoidance of prolonged fasting. In contrast to long-chain fatty acids, medium-chain fatty acids (MCFAs) are oxidized by medium-chain acyl-CoA dehydrogenase, bypassing VLCAD; therefore, MCTs may be fully metabolized, supplying the organism with the required energy. Many reports confirm the effectiveness of MCT application in the treatment of cardiomyopathy in long-chain fatty acid oxidation disorders (FAODs) (6-9). In patients with exercise-induced muscle pain, the application of an MCT bolus immediately prior to physical exercise has been proven effective (1, 5). Our own studies on the VLCAD-deficient (VLCAD / ) mouse showed the beneficial effects of MCTs when applied during increased demand (10). Although an MCT diet is considered to be a safe dietary intervention and is applied in different FAODs for longer periods of time, recent reports highlight the adverse effects of an MCT diet in the murine model of VLCAD deficiency (11)(12)(13)(14). A rather new therapeutic approach for the treatment of FAODs is represented by the application of MCTs in the form of Mitochondrial -oxidation is essential for energy production from fat. Deficiency of one of the enzymes involved is associated with life-threatening events and death. Verylong chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM 609575) is the second most common disorder of fatty acid oxidation in Europe and the USA, with an incidence of 1:25,000-1:100,000 newborns (1-4). Pathophysiological mechanisms responsible for the development of

Mitochondrial fatty acid biosynthesis and muscle fiber plasticity in very long‐chain acyl‐CoA dehydrogenase‐deficient mice

“…Similarly to MCT, triheptanoin undergoes the same metabolic degradation in the first oxidation cycle followed by the synthesis of anaplerotic five-carbon (C5) ketone bodies. However, in mice of both genotypes supplemented with this diet glucose, oxidation was upregulated as well as already reported for the heart [20]. The upregulation of glucose oxidation also in muscle clearly correlates with the upregulation of lipoic acid biosynthesis and subsequent lipoylation degree, as well as with the expression of troponine genes encoding for muscle fiber type II.…”

“…Overall, our here presented findings displayed that the upregulation of both pathways occurs in parallel to the changes in muscle fiber type. However, in mice of both genotypes supplemented with this diet glucose, oxidation was upregulated as well as already reported for the heart [20]. Therefore, a role of this pathway in metabolic regulation cannot be excluded.…”

“…Pyruvate kinase (PK) and pyruvate dehydrogenase (PDH) activities were performed in duplicate as previously reported following the manufacturer's protocol [20]. Oxidation rate of palmitoyl-CoA and citrate synthase were performed as described previously [13].…”

Cardiac tissue citric acid cycle intermediates in exercised very long‐chain acyl‐CoA dehydrogenase‐deficient mice fed triheptanoin or medium‐chain triglyceride

“…Long‐term feeding of MCT or triheptanoin chow has been associated with increased serum insulin, and hepatic steatosis, indicators of metabolic syndrome 23 . While not an aim of this study, we measured serum glucose and liver triglyceride content in all of the mice included in this study (Table S2).…”

“…Long-term feeding of MCT or triheptanoin chow has been associated with increased serum insulin, and hepatic steatosis, indicators of metabolic syndrome. 23 While not an aim of this study, we measured serum glucose and liver triglyceride content in all of the mice included in this study (Table S2). VLCAD−/− mice at exhaustion had lower serum glucose than WT mice at rest but there were no other differences in serum glucose between groups, and serum glucose was within normal ranges reported in stressed mice.…”