Very-long-chain-acyl-CoA-dehydrogenase deficiency is the most common disorder of mitochondrial long-chain
fatty acid (LCFA) oxidation, with an incidence of 1:50,000-1:100,000 in newborns. Catabolic situations contribute to the aggravation of symptoms and induce severe metabolic derangement. Treatment for
VLCAD-deficiency includes avoidance of fasting and a long-chain fat-restricted and fat-modified diet in which LCFAs are fully or partially replaced by medium-chain
triglycerides (MCT). The aim of this work was to investigate the outcome and the effects of long-term treatment in a mouse model of
VLCAD-deficiency. The application of a single MCT bolus in a mouse model of
VLCAD-deficiency (
VLCAD-/- mice) immediately prior to exercise protected the muscles from the accumulation of acylcarnitines providing the required energy and it did not affect hepatic lipid metabolism. However, when MCT was applied over the course of a year as a regular part of the diet, female
VLCAD-/- mice developed a severe clinical phenotype comparable to the human
metabolic syndrome. Indeed, they were characterized by massive visceral fat infiltration, hepatosteatosis, disturbed
fatty acid composition,
hyperlipidemia, and systemic oxidative stress. In contrast, male
VLCAD-/- mice seemed to be protected and displayed only signs of
insulin resistance. Besides the sex-specific response to MCT supplementation with regard to the lipid metabolism, all
VLCAD-/- mice developed progressive cardiac dysfunction over time which worsened when they were treated with regular MCT resulting in severe
dilated cardiomyopathy. While long term use of MCT oil in mice has adverse effects, no such effects have been demonstrated in humans, likely reflecting the differences in long chain
fatty acid oxidation between the two species.