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Journal of Lipid Research, Vol. 49, 1816-1828, August 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

GM2/GD2 and GM3 gangliosides have no effect on cellular cholesterol pools or turnover in normal or NPC1 mice

Hao Li^*, Stephen D. Turley^*, Benny Liu^*, Joyce J. Repa^*, and John M. Dietschy^1,*

^* Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, TX 75390-9151
Department of Physiology, University of Texas Southwestern Medical School, Dallas, TX 75390-9151

This work was supported by US Public Health Service Research Grant R01 HL-09610 (J.M.D., S.D.T.) and by grants from the Moss Heart Fund (J.M.D.) and The Ara Parseghian Medical Research Foundation (J.J.R.). Dr. Benny Liu also received post-doctoral support from the Ara Parseghian Medical Research Foundation and Dana's Angels Research Trust.

Published, JLR Papers in Press, April 30, 2008.

¹ To whom correspondence should be addressed. e-mail: john.dietschy{at}utsouthwestern.edu

These studies investigated the role of gangliosides in governing the steady-state concentration and turnover of unesterified cholesterol in normal tissues and in those of mice carrying the NPC1 mutation. In animals lacking either GM2/GD2 or GM3 synthase, tissue cholesterol concentrations and synthesis rates were normal in nearly all organs, and whole-animal sterol pools and turnover also were not different from control animals. Mice lacking both synthases, however, had small elevations in cholesterol concentrations in several organs, and the whole-animal cholesterol pool was marginally elevated. None of these three groups, however, had changes in any parameter of cholesterol homeostasis in the major regions of the central nervous system. When either the GM2/GD2 or GM3 synthase activity was deleted in mice lacking NPC1 function, the clinical phenotype was not changed, but lifespan was shortened. However, the abnormal cholesterol accumulation seen in the tissues of the NPC1 mouse was unaffected by loss of either synthase, and clinical and molecular markers of hepatic and cerebellar disease also were unchanged. These studies demonstrate that hydrophobic interactions between cholesterol and various gangliosides do not play an important role in determining cellular cholesterol concentrations in the normal animal or in the mouse with the NPC1 mutation.

Supplementary key words Niemann-Pick type C disease • membrane cholesterol • glycosphingolipids • neurodegeneration • cholesterol synthesis • brain cholesterol

Abbreviations: CNS, central nervous system; NPC, Niemann-Pick type C

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