Abstract
Very long-chain acyl-CoA dehydrogenase (VLCAD)-deficiency is the most common long-chain fatty acid oxidation disorder presenting with heterogeneous phenotypes. Similar to many patients with VLCADD, VLCAD-deficient mice (VLCAD−/−) remain asymptomatic over a long period of time. In order to identify the involved compensatory mechanisms, wild-type and VLCAD−/− mice were fed one year either with a normal diet or with a diet in which medium-chain triglycerides (MCT) replaced long-chain triglycerides, as approved intervention in VLCADD. The expression of the mitochondrial long-chain acyl-CoA dehydrogenase (LCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was quantified at mRNA and protein level in heart, liver and skeletal muscle. The oxidation capacity of the different tissues was measured by LC-MS/MS using acyl-CoA substrates with a chain length of 8 to 20 carbons. Moreover, in white skeletal muscle the role of glycolysis and concomitant muscle fibre adaptation was investigated. In one year old VLCAD−/− mice MCAD and LCAD play an important role in order to compensate deficiency of VLCAD especially in the heart and in the liver. However, the white gastrocnemius muscle develops alternative compensatory mechanism based on a different substrate selection and increased glucose oxidation. Finally, the application of an MCT diet over one year has no effects on LCAD or MCAD expression. MCT results in the VLCAD−/− mice only in a very modest improvement of medium-chain acyl-CoA oxidation capacity restricted to cardiac tissue. In conclusion, VLCAD−/− mice develop tissue-specific strategies to compensate deficiency of VLCAD either by induction of other mitochondrial acyl-CoA dehydrogenases or by enhancement of glucose oxidation. In the muscle, there is evidence of a muscle fibre type adaptation with a predominance of glycolytic muscle fibres. Dietary modification as represented by an MCT-diet does not improve these strategies long-term.
Highlights
Mitochondrial b-oxidation is one of the most important processes for cellular energy production
medium-chain triglycerides (MCT) effects could be seen in the liver of VLCAD2/2 mice and WT mice, whereas the heart and skeletal muscle did not show any enhancement on gene expression
In accordance with our previously published data regarding the elongation of mediumchain fatty acids as result of an MCT diet [14,17,19], we propose that the elongated fatty acid is oxidize as demonstrated by an increase in ACADL expression but cannot be shortened in sufficient amount due to deletion of VLCADD
Summary
Mitochondrial b-oxidation is one of the most important processes for cellular energy production. The first oxidation step of long-chain fatty acids (C14–20) is catalyzed by the very longchain acyl-CoA dehydrogenase (VLCAD). VLCAD-deficiency (VLCADD) is the most common long-chain fatty acid oxidation disorder with a regional incidence between 1:30,000 and 1:100,000 [2,3,4,5]. Situations of increased energy demand i.e. prolonged fasting, infectious illnesses or physical exercise, when the organism mostly relies on fatty acid b-oxidation, may trigger the development of clinical symptoms and may cause serious metabolic derangement. As part of long-term treatment and during catabolic situations, the application of sufficient carbohydrates and medium-chain triglycerides (MCT) is recommended to bypass the first step of b-oxidation catalyzed by VLCAD supplying tissues and organs with the required energy
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