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A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Author

Listed:
  • Nigel Turner

    (UNSW Sydney)

  • Xin Ying Lim

    (UNSW Sydney
    The University of Sydney)

  • Hamish D. Toop

    (UNSW Sydney)

  • Brenna Osborne

    (UNSW Sydney)

  • Amanda E. Brandon

    (University of Sydney)

  • Elysha N. Taylor

    (UNSW Sydney)

  • Corrine E. Fiveash

    (UNSW Sydney)

  • Hemna Govindaraju

    (UNSW Sydney)

  • Jonathan D. Teo

    (The University of Sydney)

  • Holly P. McEwen

    (The University of Sydney)

  • Timothy A. Couttas

    (The University of Sydney)

  • Stephen M. Butler

    (UNSW Sydney)

  • Abhirup Das

    (UNSW Sydney)

  • Greg M. Kowalski

    (Deakin University)

  • Clinton R. Bruce

    (Deakin University)

  • Kyle L. Hoehn

    (UNSW Sydney)

  • Thomas Fath

    (UNSW Sydney
    Macquarie University)

  • Carsten Schmitz-Peiffer

    (Garvan Institute of Medical Research)

  • Gregory J. Cooney

    (University of Sydney)

  • Magdalene K. Montgomery

    (UNSW Sydney)

  • Jonathan C. Morris

    (UNSW Sydney)

  • Anthony S. Don

    (The University of Sydney
    The University of Sydney)

Abstract

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.

Suggested Citation

  • Nigel Turner & Xin Ying Lim & Hamish D. Toop & Brenna Osborne & Amanda E. Brandon & Elysha N. Taylor & Corrine E. Fiveash & Hemna Govindaraju & Jonathan D. Teo & Holly P. McEwen & Timothy A. Couttas &, 2018. "A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism," Nature Communications, Nature, vol. 9(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05613-7
    DOI: 10.1038/s41467-018-05613-7
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    Cited by:

    1. Philipp Hammerschmidt & Sophie M. Steculorum & Cécile L. Bandet & Almudena Río-Martín & Lukas Steuernagel & Vivien Kohlhaas & Marvin Feldmann & Luis Varela & Adam Majcher & Marta Quatorze Correia & Rh, 2023. "CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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