Abstract
A rather new approach in the treatment of long-chain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential. We here investigate the effects of a 1-year triheptanoin-based diet on the clinical phenotype of very long-chain-acyl-CoA-dehydrogenase-deficient (VLCAD-/-) mice. The cardiac function was assessed in VLCAD-/- mice by in vivo MRI. Metabolic adaptations were identified by the expression of genes regulating energy metabolism and anaplerotic processes using real-time PCR, and the results were correlated with the measurement of the glycolytic enzymes pyruvate dehydrogenase and pyruvate kinase. Finally, the intrahepatic lipid accumulation and oxidative stress in response to the long-term triheptanoin diet were assessed. Triheptanoin was not able to prevent the development of systolic dysfunction in VLCAD-/- mice despite an upregulation of cardiac glucose oxidation. Strikingly, the anaplerotic effects of triheptanoin were restricted to the liver. Despite this, the hepatic lipic content was increased upon triheptanoin supplementation. Our data demonstrate that the concept of anaplerosis does not apply to all tissues equally.
Highlights
A rather new approach in the treatment of longchain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential
A rather new therapeutic approach for the treatment of FAODs is represented by the application of MCTs in the form of Abbreviations: KGDH, -ketoglutarate dehydrogenase; CAC, citric acid cycle; CS, citrate synthase; ESV, end-systolic volume; FAOD, fatty acid oxidation disorder; HOMA, homeostasis model assessment; MCFA, medium-chain fatty acid; MCT, medium-chain triglyceride; Pyruvate dehydrogenase (PDH), pyruvate dehydrogenase; Pyruvate kinase (PK), pyruvate kinase; SCoA, succinyl-CoA synthetase; TAG, triacylglyceride; Verylong chain acyl-CoA dehydrogenase (VLCAD), very long-chain-acyl-CoA-dehydrogenase; VLCAD /, very long-chain-acyl-CoA-dehydrogenase deficient
In mice fed the control diet, we observed a significantly reduced specific activity of the enzymes CS and KGDH in the heart of VLCAD / mice as compared with WT mice (Fig. 3A, B), which were not stimulated by triheptanoin
Summary
A rather new approach in the treatment of longchain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential. In contrast to long-chain fatty acids, medium-chain fatty acids (MCFAs) are oxidized by medium-chain acyl-CoA dehydrogenase, bypassing VLCAD; MCTs may be fully metabolized, supplying the organism with the required energy. A rather new therapeutic approach for the treatment of FAODs is represented by the application of MCTs in the form of Abbreviations: KGDH, -ketoglutarate dehydrogenase; CAC, citric acid cycle; CS, citrate synthase; ESV, end-systolic volume; FAOD, fatty acid oxidation disorder; HOMA, homeostasis model assessment; MCFA, medium-chain fatty acid; MCT, medium-chain triglyceride; PDH, pyruvate dehydrogenase; PK, pyruvate kinase; SCoA, succinyl-CoA synthetase; TAG, triacylglyceride; VLCAD, very long-chain-acyl-CoA-dehydrogenase; VLCAD / , very long-chain-acyl-CoA-dehydrogenase deficient. Our study on the long-term effects of triheptanoin supplementation in VLCAD / mice showed that, to MCTs, this diet strongly stimulates lipogenesis, resulting in a disturbed fatty acid composition of plasma membranes in liver, heart, and skeletal muscle [16]. Lipid accumulation and markers of oxidative stress were examined in the liver in addition to anaplerotic effects in heart and liver
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