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  • Title: Pharmacological regulation of cholesterol efflux in human monocyte-derived macrophages in the absence of exogenous cholesterol acceptors.
    Author: Cignarella A, Engel T, von Eckardstein A, Kratz M, Lorkowski S, Lueken A, Assmann G, Cullen P.
    Journal: Atherosclerosis; 2005 Apr; 179(2):229-36. PubMed ID: 15777536.
    Abstract:
    Cholesterol efflux from human monocyte-derived macrophages in the absence of exogenous acceptors has been described, but is unclear in mechanism. We investigated this process in relation to the expression of relevant genes, intracellular cholesterol storage and apoE secretion using drugs affecting different aspects of cholesterol metabolism. Both natural (22R-hydroxycholesterol/9-cis-retinoic acid) and synthetic (T0901317 and RO264456) LXR/RXR ligands increased ABCA1 and ABCG1 mRNAs in native macrophages and in cells loaded with acetylated LDL (acLDL). The ACAT inhibitor avasimibe increased only ABCG1 mRNA, whereas no treatment affected apoE mRNA. Avasimibe, progesterone, and natural but not synthetic LXR/RXR ligands prevented cholesterol esterification after acLDL-loading. Cholesterol efflux into acceptor-free medium was increased only by synthetic LXR/RXR ligands and avasimibe in acLDL-loaded cells. ApoE secretion was reduced by drugs affecting cholesterol trafficking but enhanced by LXR/RXR ligands. Incubation with an anti-apoE antibody virtually removed immunodetectable apoE from the medium, significantly increasing cholesterol storage and decreasing efflux. These findings indicate that in human macrophages spontaneous cholesterol efflux: (i) is not necessarily promoted by increasing intracellular free cholesterol, (ii) is increased by compounds that activate ABCA1 and, to a greater extent, ABCG1 and (iii) is only partially correlated with secretion of endogenous apoE, which acted as a cholesterol acceptor.
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