title: Overexpression of sphingosine kinase 1 in liver reduces triglyceride content in mice fed a low but not high-fat diet.
abstract: Hepatic insulin resistance is a major risk factor for the development of type 2 diabetes and is associated with the accumulation of lipids, including diacylglycerol (DAG), triacylglycerols (TAG) and ceramide. There is evidence that enzymes involved in ceramide or sphingolipid metabolism may have a role in regulating concentrations of glycerolipids such as DAG and TAG. Here we have investigated the role of sphingosine kinase (SphK) in regulating hepatic lipid levels. We show that mice on a high-fat high-sucrose diet (HFHS) displayed glucose intolerance, elevated liver TAG and DAG, and a reduction in total hepatic SphK activity. Reduced SphK activity correlated with downregulation of SphK1, but not SphK2 expression, and was not associated with altered ceramide levels. The role of SphK1 was further investigated by overexpressing this isoform in the liver of mice in vivo. On a low-fat diet (LFD) mice overexpressing liver SphK1, displayed reduced hepatic TAG synthesis and total TAG levels, but with no change to DAG or ceramide. These mice also exhibited no change in gluconeogenesis, glycogenolysis or glucose tolerance. Similarly, overexpression of SphK1 had no effect on the pattern of endogenous glucose production determined during a glucose tolerance test. Under HFHS conditions, normalization of liver SphK activity to levels observed in LFD controls did not alter hepatic TAG concentrations. Furthermore, DAG, ceramide and glucose tolerance were also unaffected. In conclusion, our data suggest that SphK1 plays an important role in regulating TAG metabolism under LFD conditions.
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia; Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, School of Biomedical Sciences, Clayton, Victoria 3800, Australia. Electronic address: greg.kowalski@deakin.edu.au.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Kowalski
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Joachim
authors.initials: J
authors.lastname: Kloehn
authors.affiliation: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, School of Biomedical Sciences, Clayton, Victoria 3800, Australia.
authors.forename: Micah L
authors.initials: ML
authors.lastname: Burch
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Ahrathy
authors.initials: A
authors.lastname: Selathurai
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Steven
authors.initials: S
authors.lastname: Hamley
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Stéphanie A M
authors.initials: SA
authors.lastname: Bayol
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia.
authors.forename: Séverine
authors.initials: S
authors.lastname: Lamon
authors.affiliation: Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, School of Biomedical Sciences, Clayton, Victoria 3800, Australia.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Watt
authors.affiliation: Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria 3004, Australia.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Lee-Young
authors.affiliation: Department of Biochemistry and Molecular Biology, Bio21 Institute of Molecular Science and Biotechnology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Malcolm J
authors.initials: MJ
authors.lastname: McConville
authors.affiliation: Centre for Physical Activity and Nutrition Research, School of Exercise and Nutrition Sciences, Deakin University, Burwood, Victoria 3125, Australia; Biology of Lipid Metabolism Laboratory, Department of Physiology, Monash University, School of Biomedical Sciences, Clayton, Victoria 3800, Australia.
authors.forename: Clinton R
authors.initials: CR
authors.lastname: Bruce
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism; D018752:Diet, Fat-Restricted; D059305:Diet, High-Fat; D004041:Dietary Fats / Q000378:metabolism*; D019422:Dietary Sucrose / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis; D008099:Liver / Q000201:enzymology*; D008297:Male; D008810:Mice, Inbred C57BL; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism*; D015854:Up-Regulation; D000099157:Sphingosine Kinase
chemical_list: D002518:Ceramides; D004041:Dietary Fats; D019422:Dietary Sucrose; D005947:Glucose; D017853:Phosphotransferases (Alcohol Group Acceptor); D012333:RNA, Messenger; D014280:Triglycerides; D000099157:Sphingosine Kinase
keywords: Ceramide; Diacylglycerol; Glucose tolerance; Liver; Sphingosine kinase 1; Triacylglycerol