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.
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.
Department of General Paediatrics, Centre for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Germany.
Sara
S
Tucci
Department of General Paediatrics, Centre for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Germany.
Sidney
S
Behringer
Department of General Paediatrics, Centre for Pediatrics and Adolescent Medicine, University Hospital Freiburg, Germany.
Ute
U
Spiekerkoetter
D044942:Acyl-CoA Dehydrogenase, Long-Chain / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000080984:Congenital Bone Marrow Failure Syndromes; D004041:Dietary Fats / Q000008:administration & dosage; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000008:administration & dosage* / Q000096:biosynthesis* / Q000737:chemistry; D005260:Female; D008052:Lipid Metabolism, Inborn Errors / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D028361:Mitochondrial Diseases / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D009135:Muscular Diseases / Q000178:diet therapy* / Q000235:genetics / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism; D014280:Triglycerides / Q000008:administration & dosage / Q000737:chemistry
D004041:Dietary Fats; D005227:Fatty Acids; D014280:Triglycerides; C531010:triheptanoin; D044942:Acyl-CoA Dehydrogenase, Long-Chain
de novo biosynthesis; elongation; medium-chain fatty acid; odd chain fatty acids; very long-chain acyl-CoA dehydrogenase deficiency