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Papers In Press, published online ahead of print October 1, 2007
J. Lipid Res., doi:10.1194/jlr.M700056-JLR200

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Journal of Lipid Research, Vol. 48, 2141-2150, October 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

Cholesterol efflux via HDL resecretion occurs when cholesterol transport out of the lysosome is impaired

Tamara A. Pagler¹, Angelika Neuhofer¹, Hildegard Laggner, Wolfgang Strobl and Herbert Stangl²

Center for Physiology and Pathophysiology, Department of Medical Chemistry, Medical University of Vienna, A-1090 Vienna, Austria

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of 4 movies.

Published, JLR Papers in Press, July 9, 2007.

¹ T. A. Pagler and A. Neuhofer contributed equally to this work.

² To whom correspondence should be addressed. e-mail: herbert.stangl{at}meduniwien.ac.at

Recently, we showed that holo HDL particle uptake and resecretion occur in physiologically relevant cell lines and that HDL uptake is mediated by scavenger receptor class B type I (SR-BI). Furthermore, we established that HDL resecretion is accompanied by [³H]cholesterol efflux. This study shows that HDL uptake and resecretion occur even when LDL uptake and cholesterol trafficking are disturbed. First, we used a set of inhibitors that block cholesterol transport out of the lysosome: chloroquine, imipramine, U18666A, and monensin. In all cases, HDL retroendocytosis occurred and HDL resecretion mediated [³H]cholesterol efflux, although to a lesser extent. Second, cell lines carrying somatic mutations in intracellular cholesterol transport were used: CHO 2-2 and CHO 3-6 cells accumulated LDL-derived lipid in the lysosome but showed all components of HDL retroendocytosis. SR-BI overexpression increased HDL uptake and resecretion and [³H]cholesterol efflux in these mutant cells. Finally, we used Niemann-Pick type C (NPC) patient fibroblast cells, which carry a defect in cholesterol transfer out of the lysosome. NPC fibroblast cells accumulate cholesterol in the lysosome as a result of a mutation in the NPC1 gene. Despite disturbed intracellular cholesterol transfer, NPC fibroblast cells exhibited HDL retroendocytosis and [³H]cholesterol efflux via HDL resecretion, although to a lesser extent. Thus, [³H]cholesterol efflux via HDL resecretion is independent of the cholesterol uptake pathway via the LDL receptor and may be an alternative way to remove excess cholesterol.

Supplementary key words scavenger receptor class B type I • high density lipoprotein • endocytosis • Niemann-Pick type C

Abbreviations: apoB, apolipoprotein B; ER, endoplasmic reticulum; FCS, fetal calf serum; NPC, Niemann-Pick type C; SR-BI, scavenger receptor class B type I

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