title: Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high-fat diet-fed mice.
abstract: The sphingolipids sphingosine-1-phosphate (S1P) and ceramide are important bioactive lipids with many cellular effects. Intracellular ceramide accumulation causes insulin resistance, but sphingosine kinase 1 (SphK1) prevents ceramide accumulation, in part, by promoting its metabolism into S1P. Despite this, the role of SphK1 in regulating insulin action has been largely overlooked. Transgenic (Tg) mice that overexpress SphK1 were fed a standard chow or high-fat diet (HFD) for 6 weeks before undergoing several metabolic analyses. SphK1 Tg mice fed an HFD displayed increased SphK activity in skeletal muscle, which was associated with an attenuated intramuscular ceramide accumulation compared with wild-type (WT) littermates. This was associated with a concomitant reduction in the phosphorylation of c-jun amino-terminal kinase, a serine threonine kinase associated with insulin resistance. Accordingly, skeletal muscle and whole-body insulin sensitivity were improved in SphK1 Tg, compared with WT mice, when fed an HFD. We have identified that the enzyme SphK1 is an important regulator of lipid partitioning and insulin action in skeletal muscle under conditions of increased lipid supply.
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
authors.forename: Steve
authors.initials: S
authors.lastname: Risis
authors.forename: Joanne R
authors.initials: JR
authors.lastname: Babb
authors.forename: Christine
authors.initials: C
authors.lastname: Yang
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kowalski
authors.forename: Ahrathy
authors.initials: A
authors.lastname: Selathurai
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.forename: Jacquelyn M
authors.initials: JM
authors.lastname: Weir
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Yoshioka
authors.forename: Yoh
authors.initials: Y
authors.lastname: Takuwa
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Pitson
authors.forename: Mark A
authors.initials: MA
authors.lastname: Febbraio
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects*; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D051379:Mice; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase