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Very long-chain acyl-CoA dehydrogenase (VLCAD-) deficiency–studies on treatment effects and long-term outcomes in mouse models

  • Metabolic Dissertation
  • Published:
Journal of Inherited Metabolic Disease

Abstract

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.

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Abbreviations

AS:

Acyl-CoA synthase

CACT:

Carnitine-acylcarnitine translocase

CK:

Creatine kinase

CPT1:

Carnitine palmitoyltransferase 1

CPT2:

Carnitine palmitoyltransferase 2

FAOD:

Fatty acid oxidation disorders

LCAD:

Long-chain acyl-CoA dehydrogenase

LCEH:

Long-chain 2,3-enoyl-CoA hydratase

LCFA:

Long-chain fatty acids

LCHAD:

Long-chain 3-hydroxyacyl-CoA dehydrogenase

LCKAT:

Long-chain β-ketoacyl-CoA thiolase

LCT:

Long-chain triglycerides

MCAD:

Medium-chain acyl-CoA dehydrogenase

MCFA:

Medium-chain fatty acids

MCKAT:

Medium-chain β-ketoacyl-CoA thiolase

MCT:

Medium-chain triglycerides

MRI:

Magnetic resonance imaging

MRS:

Magnetic resonance spectroscopy

SCAD:

Short-chain acyl-CoA dehydrogenase

SCEH:

Long-chain 2,3-enoyl-CoA hydratase

SCHAD:

Short-chain 3-hydroxyacyl-CoA dehydrogenase

SCKAT:

Short-chain β-ketoacyl-CoA thiolase

VLCAD:

Very-long-chain acyl-CoA dehydrogenase

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Acknowledgements

I am grateful to all those who have been directly and indirectly involved, namely Prof. Dr. Ute Spiekerkötter, Prof. Dr. Ulrich Flögel, Dr. Elena Borsch, Marga Sturm, Dr. Frank Ter Veld, Dr. Sonja Primassin, and Annette Seibt.

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  1. Department of General Pediatrics, Center for Pediatrics and Adolescent Medicine, Medical Centre – University of Freiburg, Mathildenstrasse 1, 79106, Freiburg, Germany

    Sara Tucci

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  1. Sara Tucci
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Correspondence to Sara Tucci.

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Sara Tucci declares that she has no conflict of interest.

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All the institutional and national guidelines for the care and use of laboratory animals were followed.

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Communicated by: Carlo Dionisi-Vici

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Tucci, S. Very long-chain acyl-CoA dehydrogenase (VLCAD-) deficiency–studies on treatment effects and long-term outcomes in mouse models. J Inherit Metab Dis 40, 317–323 (2017). https://doi.org/10.1007/s10545-017-0016-8

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  • DOI: https://doi.org/10.1007/s10545-017-0016-8

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