bruce-selectiveinhibitor-2018.pdf (1.74 MB)
A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism
journal contribution
posted on 2018-08-21, 00:00 authored by 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 KowalskiGreg Kowalski, Clinton BruceClinton Bruce, Kyle L Hoehn, Thomas Fath, Carsten Schmitz-Peiffer, Gregory J Cooney, Magdalene K Montgomery, Jonathan C Morris, Anthony S DonSpecific 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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Journal
Nature communicationsVolume
9Issue
1Article number
3165Publisher
Nature Publishing GroupLocation
London, Eng.Publisher DOI
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ISSN
2041-1723Language
engPublication classification
C1 Refereed article in a scholarly journalCopyright notice
2018, The AuthorsUsage metrics
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