1. Academic Validation
  2. 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. n.turner@unsw.edu.au.
  • 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. jonathan.morris@unsw.edu.au.
  • 12 Centenary Institute, The University of Sydney, Sydney, 2006, NSW, Australia. anthony.don@sydney.edu.au.
  • 13 NHMRC Clinical Trials Centre, Sydney Medical School, The University of Sydney, Sydney, 2006, NSW, Australia. anthony.don@sydney.edu.au.
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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