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.

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41467-018-05613-7
Journal or Publication Title: Nature Communications
Volume: 9
Number: 1
Date: 2018
Divisions: Lipid Metabolism and Neurochemistry
Depositing User: General Admin
Identification Number: 10.1038/s41467-018-05613-7
ISSN: 2041-1723
Date Deposited: 03 Jan 2021 22:47
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.

Creators:
Creators
Email
Turner, Nigel
UNSPECIFIED
Lim, Xin Ying
UNSPECIFIED
Toop, Hamish D.
UNSPECIFIED
Osborne, Brenna
UNSPECIFIED
Brandon, Amanda E.
UNSPECIFIED
Taylor, Elysha N.
UNSPECIFIED
Fiveash, Corrine E.
UNSPECIFIED
Govindaraju, Hemna
UNSPECIFIED
Teo, Jonathan D.
UNSPECIFIED
McEwen, Holly P.
UNSPECIFIED
Couttas, Timothy A.
UNSPECIFIED
Butler, Stephen M.
UNSPECIFIED
Das, Abhirup
UNSPECIFIED
Kowalski, Greg M.
UNSPECIFIED
Bruce, Clinton R.
UNSPECIFIED
Hoehn, Kyle L.
UNSPECIFIED
Fath, Thomas
UNSPECIFIED
Schmitz-Peiffer, Carsten
UNSPECIFIED
Cooney, Gregory J.
UNSPECIFIED
Montgomery, Magdalene K.
UNSPECIFIED
Morris, Jonathan C.
UNSPECIFIED
Don, Anthony S.
UNSPECIFIED
Last Modified: 03 Jan 2021 22:47
URI: https://eprints.centenary.org.au/id/eprint/524

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