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

Turner, Nigel, Lim, Xin Ying, Toop, Hamish D., Osborne, Brenna, Brandon, Amanda E., Taylor, Elysha N., Fiveash, Corrine E., Govindaraju, Hemna, Teo, Jonathan D., McEwen, Holly P., Couttas, Timothy A., Butler, Stephen M., Das, Abhirup, Kowalski, Greg M., Bruce, Clinton R., Hoehn, Kyle L., Fath, Thomas, Schmitz-Peiffer, Carsten, Cooney, Gregory J., Montgomery, Magdalene K., Morris, Jonathan C. and Don, Anthony S. 2018, A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism, Nature communications, vol. 9, no. 1, doi: 10.1038/s41467-018-05613-7.

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Title A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism
Author(s) Turner, Nigel
Lim, Xin Ying
Toop, Hamish D.
Osborne, Brenna
Brandon, Amanda E.
Taylor, Elysha N.
Fiveash, Corrine E.
Govindaraju, Hemna
Teo, Jonathan D.
McEwen, Holly P.
Couttas, Timothy A.
Butler, Stephen M.
Das, Abhirup
Kowalski, Greg M.ORCID iD for Kowalski, Greg M. orcid.org/0000-0002-1599-017X
Bruce, Clinton R.ORCID iD for Bruce, Clinton R. orcid.org/0000-0002-0515-3343
Hoehn, Kyle L.
Fath, Thomas
Schmitz-Peiffer, Carsten
Cooney, Gregory J.
Montgomery, Magdalene K.
Morris, Jonathan C.
Don, Anthony S.
Journal name Nature communications
Volume number 9
Issue number 1
Article ID 3165
Total pages 14
Publisher Nature Publishing Group
Place of publication London, Eng.
Publication date 2018-08-21
ISSN 2041-1723
Keyword(s) Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
ACTIVATED PROTEIN-KINASE
INSULIN-RESISTANCE
MITOCHONDRIAL BIOGENESIS
SKELETAL-MUSCLE
SPHINGOSINE 1-PHOSPHATE
SPHINGOLIPID METABOLISM
FTY720 ANALOGS
CHAIN LENGTH
IN-SITU
ABLATION
Summary 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.
Language eng
DOI 10.1038/s41467-018-05613-7
Field of Research MD Multidisciplinary
HERDC Research category C1 Refereed article in a scholarly journal
Copyright notice ©2018, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30113272

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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.