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Journal of Lipid Research, Vol. 49, 1677-1681, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Reduction of plasma glycosphingolipid levels has no impact on atherosclerosis in apolipoprotein E-null mice

Elias N. Glaros^*, Woojin S. Kim^*, Kerry-Anne Rye, James A. Shayman and Brett Garner^1,*,**

^* Prince of Wales Medical Research Institute, Randwick NSW 2031, Australia
The Heart Research Institute, Sydney NSW 2050, Australia
Nephrology Division, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109
^** School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney NSW 2052, Australia

This research was supported by the Australian National Health and Medical Research Council (Grant No. 350810) and a Goldstar Research Award from the University of New South Wales (Grant No. PS14703).

Published, JLR Papers in Press, May 8, 2008.

¹ To whom correspondence should be addressed. e-mail: brett.garner{at}unsw.edu.au

Glycosphingolipids (GSLs) have been implicated as potential atherogenic lipids. Studies in apolipoprotein E-null (apoE^–/–) mice indicate that exacerbated tissue GSL accumulation resulting from -galactosidase deficiency promotes atherosclerosis, whereas the serine palmitoyl transferase inhibitor myriocin (which reduces plasma and tissue levels of several sphingolipids, including sphingomyelin, ceramide, sphingosine-1-phosphate, and GSLs) inhibits atherosclerosis. It is not clear whether GSL synthesis inhibition per se has an impact on atherosclerosis. To address this issue, apoE^–/– mice maintained on a high-fat diet were treated with a potent glucosylceramide synthesis inhibitor, D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol (EtDO-P4), 10 mg/kg/day for 94 days, and lesion development was compared in mice that were treated with vehicle only. EtDO-P4 reduced plasma GSL concentration by approximately 50% but did not affect cholesterol or triglyceride levels. Assessment of atherosclerotic lesions at four different sites indicated that EtDO-P4 had no significant impact on lesion area. Thus, despite the previously observed positive correlations between plasma and aortic GSL concentrations and the development of atherosclerosis, and the in vitro evidence implying that GSLs may be pro-atherogenic, our current data indicate that inhibition of GSL synthesis does not inhibit atherosclerosis in vivo.

Supplementary key words glycosphingolipids • sphingolipids • lipid-metabolism • glycolipid synthesis inhibition • atherosclerosis therapeutics

Abbreviations: 2-AB, 2-aminobenzamide; apoE^–/–, apolipoprotein E-null mice; CTH, ceramide trihexoside; EtDO-P4, D-threo-1-ethylendioxyphenyl-2-palmitoylamino-3-pyrrolidino-propanol; GlcCer, glucosylceramide; GSL, glycosphingolipid; LacCer, lactosylceramide; NP-HPLC, normal-phase HPLC; PC, phosphatidylcholine; PLV, phospholipid vesicle; SPT, serine palmitoyl transferase; TG, triglyceride

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