De novo fatty acid biosynthesis and elongation in very long‐chain acyl‐CoA dehydrogenase‐deficient mice supplemented with odd or even medium‐chain fatty acids

Abstract

An even medium‐chain triglyceride (MCT)‐based diet is the mainstay of treatment in very long‐chain acyl‐CoA dehydrogenase (VLCAD) deficiency (VLCADD). Previous studies with magnetic resonance spectroscopy have shown an impact of MCT on the average fatty acid chain length in abdominal fat. We therefore assume that medium‐chain fatty acids (MCFAs) are elongated and accumulate in tissue as long‐chain fatty acids. In this study, we explored the hepatic effects of long‐term supplementation with MCT or triheptanoin, an odd‐chain C7‐based triglyceride, in wild‐type and VLCAD‐deficient (VLCAD−/−) mice after 1 year of supplementation as compared with a control diet. The de novo biosynthesis and elongation of fatty acids, and peroxisomal β‐oxidation, were quantified by RT‐PCR. This was followed by a comprehensive analysis of hepatic and cardiac fatty acid profiles by GC‐MS. Long‐term application of even and odd MCFAs strongly induced de novo biosynthesis and elongation of fatty acids in both wild‐type and VLCAD−/− mice, leading to an alteration of the hepatic fatty acid profiles. We detected de novo‐synthesized and elongated fatty acids, such as heptadecenoic acid (C17:1n9), eicosanoic acid (C20:1n9), erucic acid (C22:1n9), and mead acid (C20:3n9), that were otherwise completely absent in mice under control conditions. In parallel, the content of monounsaturated fatty acids was massively increased. Furthermore, we observed strong upregulation of peroxisomal β‐oxidation in VLCAD−/− mice, especially when they were fed an MCT diet. Our data raise the question of whether long‐term MCFA supplementation represents the most efficient treatment in the long term. Studies on the hepatic toxicity of triheptanoin are still ongoing.

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

“…In particular, we observed a marked increment in the content of saturated fatty acids such as C12, C14, C17, and C18. In parallel, the monounsaturated fatty acids C14:1, C16:1, and C17:1 were strongly increased, supporting previous data on the stimulation of de novo fatty acid biosynthesis and elongation (16). With the exception of C17 and C17:1, no other odd-chain species accumulated in the white adipose tissue with the long-term application, suggesting a low incorporation and processing of C7 introduced by the diet.…”

“…Indeed, the intrahepatic lipid accumulation in VLCAD / mice fed triheptanoin over 1 year was in the same range of that observed in VLCAD / mice supplemented only over 5 weeks with MCTs (14). The accumulation of long-chain acylcarnitines but not of odd-chain species indicates that the elongated fatty acids (16) are released due to energy deficiency. Indeed, MCFAs do not accumulate in white adipose tissue and are not available as energy source during higher energy demand.…”

“…The rationale behind the application of triheptanoin is that it has a potential anaplerotic effect, supplying the citric acid cycle (CAC) with the required substrates (15). Our study on the long-term effects of triheptanoin supplementation in VLCAD / mice showed that, similarly to MCTs, this diet strongly stimulates lipogenesis, resulting in a disturbed fatty acid composition of plasma membranes in liver, heart, and skeletal muscle (16). Whether triheptanoin is able to better supply all tissues with the required energy by additionally replenishing the CAC with substrates is unknown.…”

“…Fatty acid profiles have been analyzed as previously described (16). Thiobarbituric acid reactive substances have been analyzed as previously reported (11).…”

Triheptanoin treatment in patients with pediatric cardiomyopathy associated with long chain-fatty acid oxidation disorders

“…Metabolic studies in VLCAD deficiency mice have questioned the efficacy of treatment with MCT or triheptanoin. However, the relevance to VLCAD deficiency in humans is uncertain due to the concurrent expression of both long chain dehydrogenases in most mouse tissues including heart [29, 30]. …”