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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2288.)
© 2008 American Heart Association, Inc.

Cell Biology/Signaling

Liver X Receptor Activation Induces the Uptake of Cholesteryl Esters From High Density Lipoproteins in Primary Human Macrophages

Stephanie Bultel; Lionel Helin; Veronique Clavey; Giulia Chinetti-Gbaguidi; Elena Rigamonti; Morvane Colin; Jean-Charles Fruchart; Bart Staels; Sophie Lestavel

From the Institut Pasteur de Lille, Inserm, U545, and Université de Lille 2, Faculté de Pharmacie et de Médecine Lille (S.B., L.H., V.C., G.C.-G., E.R., J.-C.F., B.S., S.L.), France; and Inserm, U837 Centre de Recherche Jean-Pierre Aubert, Université de Lille 2, Faculté de Médecine, Institut de Médecine Prédictive et Recherche Thérapeutique (M.C.), Place de Verdun Lille, France.

Correspondence to Sophie Lestavel, INSERM U545, Laboratoire de recherche J et K, Faculté de Médecine Pôle Recherche, Boulevard du Professeur J. Leclercq, 59045 Lille Cedex, France. E-mail sophie.lestavel{at}univ-lille2.fr

Objective— Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported.

Methods and Results— Our results show that (1) selective CE uptake from HDL₃ is highly efficient in human monocyte-derived macrophages; (2) surprisingly, HDL₃-CE uptake is strongly increased by LXR activation despite antiatherogenic effects of LXRs; (3) HDL₃-CE uptake increase is not linked to SR-BI expression modulation but it is dependent of proteoglycan interactions; (4) HDL₃-CE uptake increase is associated with increased expression and secretion of apoE and LPL, two proteins interacting with proteoglycans; (5) HDL₃-CE uptake increase depends on the integrity of raft domains and is associated with an increased caveolin-1 expression.

Conclusions— Our study identifies a new role for LXRs in the control of cholesterol homeostasis in human macrophages. LXR activation results in enhanced dynamic intracellular cholesterol fluxes through an increased CE uptake from HDL and leads to an increased cholesterol availability to efflux to apoAI and HDL.

Our aim was to study whether, beside their known role in promoting cholesterol efflux from macrophages, the nuclear receptors LXR could also regulate cholesterol uptake from lipoproteins. In human macrophages, LXR activation strongly increases HDL-cholesteryl ester uptake by enhancing apoE and LPL secretion. These LXR effects require proteoglycans, raft integrity, and are correlated with caveolin-1 upregulation.

Key Words: liver X receptors • cholesteryl ester uptake • primary human macrophages

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