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Unique plasma metabolomic signatures of individuals with inherited disorders of long-chain fatty acid oxidation

  • Original Article
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Journal of Inherited Metabolic Disease

Abstract

Blood and urine acylcarnitine profiles are commonly used to diagnose long-chain fatty acid oxidation disorders (FAOD: i.e., long-chain hydroxy-acyl-CoA dehydrogenase [LCHAD] and carnitine palmitoyltransferase 2 [CPT2] deficiency), but the global metabolic impact of long-chain FAOD has not been reported. We utilized untargeted metabolomics to characterize plasma metabolites in 12 overnight-fasted individuals with FAOD (10 LCHAD, two CPT2) and 11 healthy age-, sex-, and body mass index (BMI)-matched controls, with the caveat that individuals with FAOD consume a low-fat diet supplemented with medium-chain triglycerides (MCT) while matched controls consume a typical American diet. In plasma 832 metabolites were identified, and partial least squared-discriminant analysis (PLS-DA) identified 114 non-acylcarnitine variables that discriminated FAOD subjects and controls. FAOD individuals had significantly higher triglycerides and lower specific phosphatidylethanolamines, ceramides, and sphingomyelins. Differences in phosphatidylcholines were also found but the directionality differed by metabolite species. Further, there were few differences in non-lipid metabolites, indicating the metabolic impact of FAOD specifically on lipid pathways. This analysis provides evidence that LCHAD/CPT2 deficiency significantly alters complex lipid pathway flux. This metabolic signature may provide new clinical tools capable of confirming or diagnosing FAOD, even in subjects with a mild phenotype, and may provide clues regarding the biochemical and metabolic impact of FAOD that is relevant to the etiology of FAOD symptoms.

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Acknowledgments

The authors would like to thank Dr. Oliver Fiehn of the West Coast Metabolomics Center at UC Davis for his support of the metabolomics and lipidomics analysis. The West Coast Metabolomics Center is supported by NIH Grant U24 DK097154. Additionally, the authors would like to thank Dr. John Newman of the USDA Western Human Nutrition Research Center for his support in interpretation of the lipidomics analysis as well as Dr. Paul Coen of the Translational Research Institute for Metabolism and Diabetes for his insightful comments and review of this manuscript. The genesis of this project emerged from results from grants awarded by the NIH-NIDDK (R01DK078328 and R01DK078328-02S1, to S.H.A. and K01DK071869, to M.G.) and USDA-ARS intramural Project 5306-51530-019-00, and the studies supported by a UC Davis Clinical and Translational Science Center (CTSC) Pilot Award (to S.H.A., J.V., M.G.) funded by the NIH National Center for Advancing Translational Sciences, through grant number UL1TR000002. This project was also supported by a NIH T32 pre-doctoral training award (to C.S.M.), funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number UL1 TR000002 and linked award TL1 TR000133. J.V. was supported in part by R01-DK78755. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

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    Authors and Affiliations

    1. Molecular, Cellular and Integrative Physiology Graduate Group, University of California, Davis, CA, USA

      Colin S. McCoin & Sean H. Adams

    2. Arkansas Children’s Nutrition Center and Department of Pediatrics, University of Arkansas for Medical Sciences, 15 Children’s Way, Little Rock, AR, 72202, USA

      Brian D. Piccolo & Sean H. Adams

    3. Department of Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA

      Trina A. Knotts

    4. Biochemical Genetics Laboratory, Mayo Clinic, Rochester, MN, USA

      Dietrich Matern

    5. Department of Pediatrics, School of Medicine, Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA, USA

      Jerry Vockley

    6. Department of Human Genetics, Graduate School of Public Health, Pittsburgh, PA, USA

      Jerry Vockley

    7. Department of Molecular & Medical Genetics and Graduate Programs in Human Nutrition, Oregon Health & Science University, Portland, OR, USA

      Melanie B. Gillingham

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    1. Colin S. McCoin
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    Corresponding author

    Correspondence to Sean H. Adams.

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    Informed consent

    All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Written informed consent was obtained from all patients or legal guardians prior to inclusion in the study.

    Additional information

    Communicated by: Ronald JA Wanders

    Colin S. McCoin and Brian D. Piccolo contributed equally to this work.

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    Supplemental Table 1

    Complete data set containing quantifier ion peak heights (QIPH) for untargeted plasma metabolomics and lipidomics from healthy control subjects (n = 11) and individuals with FAOD diagnosed with LCHAD (n = 10) or CPT2 (n = 2) (XLSX 428 kb)

    Supplemental Table 2

    Bootstrapped variable importance in projection (VIP) statistics from partial least squared-discriminant analyses (PLS-DA) of Model 1 and Model 2 from plasma of healthy control (n = 11) and FAOD (n = 12) individuals with FAOD (XLSX 39.3 kb)

    Supplemental Table 3

    Diagnostic and supplementation information for FAOD subjects (XLSX 14 kb)

    Supplemental Table 4

    Plasma acylcarnitine analysis performed on 10 h fasted FAOD and healthy control subjects (XLSX 14 kb)

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    McCoin, C.S., Piccolo, B.D., Knotts, T.A. et al. Unique plasma metabolomic signatures of individuals with inherited disorders of long-chain fatty acid oxidation. J Inherit Metab Dis 39, 399–408 (2016). https://doi.org/10.1007/s10545-016-9915-3

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    • DOI: https://doi.org/10.1007/s10545-016-9915-3

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