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; Anthony S. Don

doi:10.1038/s41467-018-05613-7

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 & 2 others Jonathan C. Morris, Anthony S. Don

^*Corresponding author for this work

Research output: Contribution to journal › Article

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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.

Original language	English
Article number	3165
Number of pages	14
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-05613-7
Publication status	Published - 1 Dec 2018
Externally published	Yes

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Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Turner, N., Lim, X. Y., Toop, H. D., Osborne, B., Brandon, A. E., Taylor, E. N., ... Don, A. S. (2018). A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism. Nature Communications, 9(1), [3165]. https://doi.org/10.1038/s41467-018-05613-7

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. ; Don, Anthony S. / A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism. In: Nature Communications. 2018 ; Vol. 9, No. 1.

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title = "A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism",

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.",

author = "Nigel Turner and Lim, {Xin Ying} and Toop, {Hamish D.} and Brenna Osborne and Brandon, {Amanda E.} and Taylor, {Elysha N.} and Fiveash, {Corrine E.} and Hemna Govindaraju and Teo, {Jonathan D.} and McEwen, {Holly P.} and Couttas, {Timothy A.} and Butler, {Stephen M.} and Abhirup Das and Kowalski, {Greg M.} and Bruce, {Clinton R.} and Hoehn, {Kyle L.} and Thomas Fath and Carsten Schmitz-Peiffer and Cooney, {Gregory J.} and Montgomery, {Magdalene K.} and Morris, {Jonathan C.} and Don, {Anthony S.}",

note = "Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2018",

month = "12",

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doi = "10.1038/s41467-018-05613-7",

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Turner, N, Lim, XY, Toop, HD, Osborne, B, Brandon, AE, Taylor, EN, Fiveash, CE, Govindaraju, H, Teo, JD, McEwen, HP, Couttas, TA, Butler, SM, Das, A, Kowalski, GM, Bruce, CR, Hoehn, KL, Fath, T, Schmitz-Peiffer, C, Cooney, GJ, Montgomery, MK, Morris, JC & Don, AS 2018, 'A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism', Nature Communications, vol. 9, no. 1, 3165. https://doi.org/10.1038/s41467-018-05613-7

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.; Don, Anthony S.

In: Nature Communications, Vol. 9, No. 1, 3165, 01.12.2018.

Research output: Contribution to journal › Article

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AU - Turner, Nigel

AU - Lim, Xin Ying

AU - Toop, Hamish D.

AU - Osborne, Brenna

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AU - Taylor, Elysha N.

AU - Fiveash, Corrine E.

AU - Govindaraju, Hemna

AU - Teo, Jonathan D.

AU - McEwen, Holly P.

AU - Couttas, Timothy A.

AU - Butler, Stephen M.

AU - Das, Abhirup

AU - Kowalski, Greg M.

AU - Bruce, Clinton R.

AU - Hoehn, Kyle L.

AU - Fath, Thomas

AU - Schmitz-Peiffer, Carsten

AU - Cooney, Gregory J.

AU - Montgomery, Magdalene K.

AU - Morris, Jonathan C.

AU - Don, Anthony S.

N1 - Copyright the Author(s) 2018. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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10.1038/s41467-018-05613-7

Publisher version (open access)Final published version, 1 MBLicence: CC BY

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