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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1923.)
© 2009 American Heart Association, Inc.

Cell Biology/Signaling

Liver X Receptor–Mediated Induction of Cholesteryl Ester Transfer Protein Expression Is Selectively Impaired in Inflammatory Macrophages

Daniela Lakomy; Cédric Rébé; Anne-Laure Sberna; David Masson; Thomas Gautier; Angélique Chevriaux; Magalie Raveneau; Nicolas Ogier; Anh Thoai Nguyen; Philippe Gambert; Jacques Grober; Bernard Bonnotte; Eric Solary; Laurent Lagrost

From INSERM UMR866-Université de Bourgogne (D.L., C.R., A.L.S., D.M., T.G., N.O., A.T.N., P.G., J.G., B.B., E.S., L.L.), IFR Santé-STIC (D.L., C.R., A.L.S., D.M., T.G., A.C., M.R., N.O., A.T.N., P.G., J.G., B.B., E.S., L.L.), and Centre Georges-François Leclerc (CR) Dijon Cedex, France.

Correspondence to Laurent Lagrost, INSERM UMR866, Faculté de Médecine, BP87900, 21079 Dijon Cedex, France. E-mail laurent. lagrost{at}u-bourgogne.fr

Objective— Cholesteryl ester transfer protein (CETP) is a target gene for the liver X receptor (LXR). The aim of this study was to further explore this regulation in the monocyte-macrophage lineage and its modulation by lipid loading and inflammation, which are key steps in the process of atherogenesis.

Methods and Results— Exposure of bone marrow–derived macrophages from human CETP transgenic mice to the T0901317 LXR agonist increased CETP, PLTP, and ABCA1 mRNA levels. T0901317 also markedly increased CETP mRNA levels and CETP production in human differentiated macrophages, whereas it had no effect on CETP expression in human peripheral blood monocytes. In inflammatory mouse and human macrophages, LXR-mediated CETP gene upregulation was inhibited, even though ABCA1, ABCG1, and SREBP1c inductions were maintained. The inhibition of CETP gene response to LXR agonists in inflammatory cells was independent of lipid loading (ie, oxidized LDL increased CETP production in noninflammatory macrophages with a synergistic effect of synthetic LXR agonists).

Conclusion— LXR-mediated induction of human CETP expression is switched on during monocyte-to-macrophage differentiation, is magnified by lipid loading, and is selectively lost in inflammatory macrophages, which suggests that inflammatory cells may not increase the circulating CETP pool on LXR agonist treatment.

In the monocyte-macrophage lineage, both in mice and humans, LXR-mediated induction of CETP gene expression is switched on during monocyte-to-macrophage differentiation, magnified by lipid loading, and selectively lost when macrophages become inflammatory.

Key Words: liver X receptor • cholesteryl ester transfer protein • macrophage • monocyte • inflammation