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Selective Activation of Liver X Receptors by Acanthoic Acid-Related Diterpenes

Centro Nacional de Investigaciones Cardiovasculares and Instituto de Investigaciones Biomédicas Alberto Sols, Madrid, Spain (P.G.T., S.H., M.Z., L.B.); Nereus Pharmaceuticals, Inc., San Diego, California (T.-H.C., S.T.N., M.A.P.); Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California (T.L., E.A.T.); and Departamento Bioquimica y Biologia Molecular, Universidad Las Palmas, Las Palmas, Spain (A.C.)

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 and LXR) 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). 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,^–/–). 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.

Address correspondence to: Dr. Antonio Castrillo, Dpto. Bioquimica y Biologia Molecular, Facultad de Medicina, Universidad de Las Palmas, 35016 Las Palmas, Spain. E-mail: acastrillo{at}ramonycajal.ulpgc.es

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