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

• Published in: The FEBS journal 2015-11, Vol.282 (21), p.4242-4253
• Main Authors: Tucci, Sara, Behringer, Sidney, Spiekerkoetter, Ute
• Format: Article
• Language: English
• Subjects: Acyl-CoA Dehydrogenase, Long-Chain - deficiency; Acyl-CoA Dehydrogenase, Long-Chain - genetics; Acyl-CoA Dehydrogenase, Long-Chain - metabolism; Animals; de novo biosynthesis; Dietary Fats - administration & dosage; Disease Models, Animal; elongation; Fatty Acids - administration & dosage; Fatty Acids - biosynthesis; Fatty Acids - chemistry; Female; Lipid Metabolism, Inborn Errors - diet therapy; Lipid Metabolism, Inborn Errors - genetics; Lipid Metabolism, Inborn Errors - metabolism; Liver - metabolism; Male; medium‐chain fatty acid; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Knockout; Mitochondrial Diseases - diet therapy; Mitochondrial Diseases - genetics; Mitochondrial Diseases - metabolism; Muscular Diseases - diet therapy; Muscular Diseases - genetics; Muscular Diseases - metabolism; Myocardium - metabolism; odd chain fatty acids; Oxidation-Reduction; Peroxisomes - metabolism; Triglycerides - administration & dosage; Triglycerides - chemistry; very long‐chain acyl‐CoA dehydrogenase deficiency
• ISSN: 1742-464X; 1742-4658
• DOI: 10.1111/febs.13418

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. Long‐term application of MCT and Triheptanoin as mainstay of treatment in VLCAD‐deficiency strongly induces de novo biosynthesis and elongation of fatty acids in VLCAD−/− mice leading to an alteration of the hepatic fatty acids profiles resulting in species completely absent in mice under control conditions. In parallel, the content of monounsaturated fatty acids is massively increased.