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Title: Selective activation of liver X receptors by acanthoic acid-related diterpenes
Authors: Traves, Paqui G.
Hortelano, Sonsoles
Zeini, Miriam
Chao, Ta Hsiang
Lam, Thanh
Neuteboom, Saskia T.
Theodorakis, Emmanuel A.
Palladino, Michael A.
Castrillo, Antonio 
Bosca, Lisardo
Keywords: Lxr-Alpha
Nuclear Receptors
Oxysterol Receptors
Rxr Heterodimers, et al
Issue Date: 2007
Publisher: 0026-895X
Journal: Molecular Pharmacology 
Abstract: Terpenoids constitute a large family of natural steroids that are widely distributed in plants and insects. We investigated the effects of a series of diterpenes structurally related to acanthoic acid in macrophage functions. We found that diterpenes with different substitutions at the C4 position in ring A are potent activators of liver X receptors (LXR alpha and LXR beta) in both macrophage cell lines from human and mouse origin and primary murine macrophages. Activation of LXR by these diterpenes was evaluated in transient transfection assays and gene expression analysis of known LXR-target genes, including the cholesterol transporters ABCA1 and ABCG1, the sterol regulatory element-binding protein 1c, and the apoptosis inhibitor of macrophages (Sp alpha). Moreover, active diterpenes greatly stimulated cholesterol efflux from macrophages. It is interesting that these diterpenes antagonize inflammatory gene expression mainly through LXR-dependent mechanisms, indicating that these compounds can activate both LXR activation and repression functions. Stimulation of macrophages with acanthoic acid diterpenes induced LXR-target gene expression and cholesterol efflux to similar levels observed with synthetic agonists 3-[3-[N-(2-chloro-3-trifluoromethylbenzyl)-(2,2-diphenylethyl)amino] propyloxy] phenylacetic acid hydrochloride (GW3965) and N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl] phenyl]-benzenesulfonamide [T1317 (T0901317)]. These effects observed in gene expression were deficient in macrophages lacking both LXR isoforms (LXR alpha, beta(-/-)). These results show the ability of certain acanthoic acid diterpenes to activate efficiently both LXRs and suggest that these compounds can exert beneficial effects from a cardiovascular standpoint through LXR-dependent mechanisms.
ISSN: 0026-895X
DOI: 10.1124/mol.106.031906
Source: Molecular Pharmacology[ISSN 0026-895X],v. 71, p. 1545-1553
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