2. Academic Validation
  3. A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

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

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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