PT - JOURNAL ARTICLE AU - Paqui G. Traves AU - Sonsoles Hortelano AU - Miriam Zeini AU - Ta-Hsiang Chao AU - Thanh Lam AU - Saskia T. Neuteboom AU - Emmanuel A. Theodorakis AU - Michael A. Palladino AU - Antonio Castrillo AU - Lisardo Bosca TI - Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes AID - 10.1124/mol.106.031906 DP - 2007 Jun 01 TA - Molecular Pharmacology PG - 1545--1553 VI - 71 IP - 6 4099 - http://molpharm.aspetjournals.org/content/71/6/1545.short 4100 - http://molpharm.aspetjournals.org/content/71/6/1545.full SO - Mol Pharmacol2007 Jun 01; 71 AB - 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 (LXRα and LXRβ) 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 (Spα). 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 (LXRα,β–/–). 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. The American Society for Pharmacology and Experimental Therapeutics