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

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, Stephen M. Butler, Abhirup Das, Greg M. Kowalski, Clinton R. Bruce, Kyle L. Hoehn, Thomas Fath, Carsten Schmitz-Peiffer, Gregory J. Cooney, Magdalene K. Montgomery, Jonathan C. Morris () and Anthony S. Don ()
Additional contact information
Nigel Turner: UNSW Sydney
Xin Ying Lim: UNSW 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
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

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05613-7

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