Sie befinden Sich nicht im Netzwerk der Universität Paderborn. Der Zugriff auf elektronische Ressourcen ist gegebenenfalls nur via VPN oder Shibboleth (DFN-AAI) möglich. mehr Informationen...
United States: American Society for Pharmacology and Experimental Therapeutics
Erscheinungsjahr
2007
Quelle
MEDLINE
Beschreibungen/Notizen
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 â/â ). 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.