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Journal of Lipid Research, Vol. 47, 51-58, January 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

Reevaluation of the role of the multidrug-resistant P-glycoprotein in cellular cholesterol homeostasis

Wilfried Le Goff^*,, Megan Settle^*, Diane J. Greene^*, Richard E. Morton^*, and Jonathan D. Smith^1,*,

^* Department of Cell Biology NC10, Cleveland Clinic Foundation, Cleveland, OH
Institut National de la Santé et de la Recherche Médicale Unit 551, Dyslipoproteinemia and Atherosclerosis, Hôpital de la Pitié, Paris, France
Department of Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, OH

Published, JLR Papers in Press, October 7, 2005.

¹ To whom correspondence should be addressed. e-mail:smithj4{at}.ccf.org

The multidrug resistance P-glycoprotein (P-gp) was recently proposed to redistribute cholesterol in the plasma membrane, suggesting that P-gp could modulate cholesterol efflux to cholesterol acceptors. To address this hypothesis and to reevaluate the role of P-gp in cholesterol homeostasis, we first analyzed the role of P-gp expression on cholesterol efflux in P-gp stably transfected drug-selected LLC-MDR1 cells. Cholesterol efflux to methyl-ß-cyclodextrin (CD) was 4-fold higher in LLC-MDR1 cells compared with control LLC-PK1 cells, indicating that the accessible pool of plasma membrane cholesterol was increased by P-gp expression. However, using the P-gp-inducible cells lines HeLa MDR-Tet and 77.1 MDR-Tet, cholesterol efflux to CD, apolipoprotein A-I, or HDL was not associated with P-gp expression. In addition, we did not observe any effect of P-gp expression on cellular free and esterified cholesterol content, cholesteryl ester uptake from LDL and HDL particles, or acyl-CoA:cholesterol acyltransferase activity. Therefore, we conclude that P-gp expression does not play a major role in cholesterol homeostasis in P-gp-inducible cells and that the effects of P-gp on cholesterol homeostasis previously described in drug-selected cells might result from non-P-gp pathways that were also induced by selection for drug resistance.

Supplementary key words cholesterol efflux • ABCA1 • cyclodextrin • apolipoprotein A-I

Abbreviations: apoA-I, apolipoprotein A-I; CD, methyl-ß-cyclodextrin; CE, cholesteryl ester; COE, cholesteryl oleyl ether; DAPI, 4',6-diamidino-2-phenylindole; FC, free cholesterol; MDR, multidrug resistance; P-gp, P-glycoprotein; Rho-123, rhodamine 123

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