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

  • Nat Commun. 2018 Aug 21;9(1):3165. doi: 10.1038/s41467-018-05613-7.
Nigel Turner  1 ,  Xin Ying Lim  2  3 ,  Hamish D Toop  4 ,  Brenna Osborne  5 ,  Amanda E Brandon  6 ,  Elysha N Taylor  4 ,  Corrine E Fiveash  5 ,  Hemna Govindaraju  5 ,  Jonathan D Teo  3 ,  Holly P McEwen  3 ,  Timothy A Couttas  3 ,  Stephen M Butler  4 ,  Abhirup Das  5 ,  Greg M Kowalski  7 ,  Clinton R Bruce  7 ,  Kyle L Hoehn  8 ,  Thomas Fath  5  9 ,  Carsten Schmitz-Peiffer  10 ,  Gregory J Cooney  6 ,  Magdalene K Montgomery  5 ,  Jonathan C Morris  11 ,  Anthony S Don  12  13
Affiliations
  • 1. School of Medical Sciences, UNSW Sydney, Sydney, 2052, NSW, Australia. [email protected].
  • 2. Prince of Wales Clinical School, Faculty of Medicine, UNSW Sydney, Sydney, 2052, NSW, Australia.
  • 3. Centenary Institute, The University of Sydney, Sydney, 2006, NSW, Australia.
  • 4. School of Chemistry, UNSW Sydney, Sydney, 2052, NSW, Australia.
  • 5. School of Medical Sciences, UNSW Sydney, Sydney, 2052, NSW, Australia.
  • 6. Sydney Medical School, Charles Perkins Centre, University of Sydney, Sydney, 2006, NSW, Australia.
  • 7. Institute for Physical Activity and Nutrition, School of Exercise and Nutrition Sciences, Deakin University, Burwood, 3125, VIC, Australia.
  • 8. School of Biotechnology and Biomolecular Sciences, UNSW Sydney, Sydney, 2052, NSW, Australia.
  • 9. Department of Biomedical Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
  • 10. Garvan Institute of Medical Research, Sydney, 2010, NSW, Australia.
  • 11. School of Chemistry, UNSW Sydney, Sydney, 2052, NSW, Australia. [email protected].
  • 12. Centenary Institute, The University of Sydney, Sydney, 2006, NSW, Australia. [email protected].
  • 13. NHMRC Clinical Trials Centre, Sydney Medical School, The University of Sydney, Sydney, 2006, NSW, Australia. [email protected].
PMID: 30131496 DOI: 10.1038/s41467-018-05613-7
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.

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