title: Knock-down of the oxysterol receptor LXRα impairs cholesterol efflux in human primary macrophages: lack of compensation by LXRβ activation.
abstract: Liver X Receptors (LXRs) α and β are oxysterol-activated nuclear receptors involved in the control of lipid metabolism and inflammation. Pharmacological activation of LXR is promising in the treatment of atherosclerosis since it can promote cholesterol efflux from macrophages and prevent foam cell formation. However, the development of LXR agonists has been limited by undesirable side-effects such as hepatic steatosis mediated by LXRα activation. Therefore, it has been proposed that targeting LXRα activators to extrahepatic tissues or using LXRβ-specific activators could be used as alternative strategies. It is not clear whether these molecules will retain the full atheroprotective potential of non-selective agonists. Our aim was therefore to determine the contribution of LXRα and LXRβ to the control of cholesterol efflux in human macrophages. LXRα and/or LXRβ expression was suppressed by small interfering RNAs in human primary macrophages treated or not with synthetic LXRα/β dual agonists T0901317 and GW3965. We observed that LXRβ silencing had no detectable impact on the expression of LXR-target genes such as ABCA1 and ABCG1. Moreover it did not affect cholesterol efflux. In contrast, LXRα silencing reduced the response of these LXR-target genes to LXR agonist and inhibited cholesterol efflux to ApoA-I, HDL2 or to endogenous ApoE. Importantly, no differences were observed between LXRα and LXRα/β knockdown conditions. Altogether, our data demonstrate that LXRβ activation is unable to maintain maximal cholesterol efflux capacities in human primary macrophages when LXRα expression is impaired. In contrast to earlier mouse studies, LXRα levels appear as a limiting factor for macrophage cholesterol efflux in humans.
authors: Centre de Recherche INSERM-UMR866, Faculté de Médecine, Université de Bourgogne, 21079 Dijon cedex, France.
authors: Minako
authors: M
authors: Ishibashi
authors: Rodolphe
authors: R
authors: Filomenko
authors: Cédric
authors: C
authors: Rébé
authors: Angélique
authors: A
authors: Chevriaux
authors: Alexis
authors: A
authors: Varin
authors: Valentin
authors: V
authors: Derangère
authors: Ginette
authors: G
authors: Bessède
authors: Philippe
authors: P
authors: Gambert
authors: Laurent
authors: L
authors: Lagrost
authors: David
authors: D
authors: Masson
mesh_terms: D016632:Apolipoprotein A-I / Q000378:metabolism; D001057:Apolipoproteins E / Q000378:metabolism; D001565:Benzoates / Q000494:pharmacology; D001596:Benzylamines / Q000494:pharmacology; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology; D053439:Lipoproteins, HDL2 / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D001565:Benzoates; D001596:Benzylamines; D002784:Cholesterol; D006845:Hydrocarbons, Fluorinated; D053439:Lipoproteins, HDL2; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D034741:RNA, Small Interfering; D013449:Sulfonamides; C473027:GW 3965; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides