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Nat Commun. 2018 Aug 21;9(1):3165. doi: 10.1038/s41467-018-05613-7.

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

Author information

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.

PMID:
30131496
PMCID:
PMC6104039
DOI:
10.1038/s41467-018-05613-7
[Indexed for MEDLINE]
Free PMC Article

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