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

被引：101

作者：

Turner, Nigel ^{[1
]}

Lim, Xin Ying ^{[2
,3
]}

Toop, Hamish D. ^{[4
]}

Osborne, Brenna ^{[1
]}

Brandon, Amanda E. ^{[5
]}

Taylor, Elysha N. ^{[4
]}

Fiveash, Corrine E. ^{[1
]}

Govindaraju, Hemna ^{[1
]}

Teo, Jonathan D. ^{[3
]}

McEwen, Holly P. ^{[3
]}

Couttas, Timothy A. ^{[3
]}

Butler, Stephen M. ^{[4
]}

Das, Abhirup ^{[1
]}

Kowalski, Greg M. ^{[6
]}

Bruce, Clinton R. ^{[6
]}

Hoehn, Kyle L. ^{[7
]}

Fath, Thomas ^{[1
,10
]}

Schmitz-Peiffer, Carsten ^{[8
]}

Cooney, Gregory J. ^{[5
]}

Montgomery, Magdalene K. ^{[1
]}

Morris, Jonathan C. ^{[4
]}

Don, Anthony S. ^{[3
,9
]}

机构：

[1] UNSW Sydney, Sch Med Sci, Sydney, NSW 2052, Australia

[2] UNSW Sydney, Fac Med, Prince Wales Clin Sch, Sydney, NSW 2052, Australia

[3] Univ Sydney, Centenary Inst, Sydney, NSW 2006, Australia

[4] UNSW Sydney, Sch Chem, Sydney, NSW 2052, Australia

[5] Univ Sydney, Sydney Med Sch, Charles Perkins Ctr, Sydney, NSW 2006, Australia

[6] Deakin Univ, Sch Exercise & Nutr Sci, Inst Phys Act & Nutr, Burwood, Vic 3125, Australia

[7] UNSW Sydney, Sch Biotechnol & Biomol Sci, Sydney, NSW 2052, Australia

[8] Garvan Inst Med Res, Sydney, NSW 2010, Australia

[9] Univ Sydney, Sydney Med Sch, NHMRC Clin Trials Ctr, Sydney, NSW 2006, Australia

[10] Macquarie Univ, Dept Biomed Sci, Sydney, NSW 2109, Australia

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

ACTIVATED PROTEIN-KINASE; INSULIN-RESISTANCE; MITOCHONDRIAL BIOGENESIS; SKELETAL-MUSCLE; SPHINGOSINE; 1-PHOSPHATE; SPHINGOLIPID METABOLISM; FTY720; ANALOGS; CHAIN LENGTH; IN-SITU; ABLATION;

D O I：

10.1038/s41467-018-05613-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：14

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