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J. Biol. Chem., Vol. 280, Issue 43, 36126-36131, October 28, 2005

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Activation of Membrane Cholesterol by Displacement from Phospholipids^*

Yvonne Lange1, Jin Ye, and Theodore L. Steck

From the Department of Pathology, Rush University Medical Center, Chicago, Illinois 60612 and the Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, Illinois 60637

We tested the hypothesis that certain membrane-intercalating agents increase the chemical activity of cholesterol by displacing it from its low activity association with phospholipids. Octanol, 1,2-dioctanoyl-sn-glycerol (a diglyceride), and N-hexanoyl-D-erythrosphingosine (a ceramide) were shown to increase both the rate of transfer and the extent of equilibrium partition of human red blood cell cholesterol to methyl--cyclodextrin. These agents also promoted the interaction of the sterol with two cholesterol-specific probes, cholesterol oxidase and saponin. Expanding the pool of bilayer phospholipids with lysophosphatides countered these effects. The three intercalators also protected the red cells against lysis by cholesterol depletion as if substituting for the extracted sterol. As is the case for excess plasma membrane cholesterol, treating human fibroblasts with octanol, diglyceride, or ceramide stimulated the rapid inactivation of their hydroxymethylglutaryl-CoA reductase, presumably through an increase in the pool of endoplasmic reticulum cholesterol. These data supported the stated hypothesis and point to competition between cholesterol and endogenous and exogenous intercalators for association with membrane phospholipids. We also describe simple screens using red cells in a microtiter well format to identify intercalating agents that increase or decrease the activity of membrane cholesterol.

Received for publication, June 30, 2005 , and in revised form, August 23, 2005.

^* This work was supported by National Institutes of Health Grant HL 28448. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Pathology, Rush University Medical Center, 1653 West Congress Pkwy., Chicago, IL 60612. Tel.: 312-942-5256; Fax: 312-563-3115; E-mail: ylange{at}rush.edu.

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