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Overexpression of sphingosine kinase 1 in liver reduces triglyceride content in mice fed a low but not high-fat diet

Version 2 2024-06-04, 03:32
Version 1 2015-01-15, 11:09
journal contribution
posted on 2024-06-04, 03:32 authored by Greg KowalskiGreg Kowalski, Joachim Kloehn, Micah L Burch, Ahrathy SelathuraiAhrathy Selathurai, Steven Hamley, Stéphanie AM Bayol, Severine LamonSeverine Lamon, Matthew J Watt, Robert S Lee-Young, Malcolm J McConville, Clinton BruceClinton Bruce
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.

History

Journal

Biochimica et Biophysica Acta (BBA)- molecular and cell biology of lipids

Volume

1851

Pagination

210-219

Location

Amsterdam, Netherlands

ISSN

1388-1981

Language

eng

Publication classification

C Journal article, C1 Refereed article in a scholarly journal

Copyright notice

2015, Elsevier BV

Issue

2

Publisher

Elsevier BV