Cholestenoic Acid analog (27-Norcholestenoic) effects over Liver X Receptor (LXR) activity

NAVALESI D.; GRINMAN D.; DANSEY V.; PECCI A.

Bariloche

Simposio; 3rd South American Symposium in Signal Transduction and Molecular Medicine; 2015

SISTAM

Liver X Receptors (LXRα and β) are transcriptional factors that belong to the oxysterols-activated nuclear receptors superfamily. They are involved in the control of physiological functions such as lipid metabolism, proliferation and apoptosis. In mammary gland, LXRs are thought not only to regulate milk lipid synthesis and secretion during lactation but also to have antiproliferative and proapoptotic effects over epithelial cells. Numerous evidences link this effects to LXR activity as a lipid homeostasis modulator. Here we show the actions of the novel ligand 27-norcholestenoic (27-norchol), a cholestenoic acid analog, on the expression of genes involved in cholesterol reverse transport and triglycerides synthesis, in normal (HC11) and tumoral (T47D and HEPG2) cell lines. All of them express both LXR isoforms. In T47D cells a 18 hs incubation with GW3965, a commercial synthetic LXR agonist, induced the expression of the canonical lipid homeostasis genes SREBP1 (sterol regulatory element-binding protein 1) 2.36 ± 0.58 fold vs control, ABCA1 (ATP-binding cassette transporter) 6.51 ± 1.41 fold, ApoE (Apolipoprotein E) 1.29 ± 0.28 fold and FAS (Fatty acid synthase) 2.30 ± 0.48 fold, while coincubation with 27-norchol antagonized GW3965-mediated FAS induction and stimulated ApoE expression. At the same time, 27-norchol acted as an antagonist and inverse agonist in HC11 and HEPG2 cells when incubated with GW3965 or alone, respectively, over FAS and ABCA1 expression. According to these results, this novel ligand would present a differential effect over cholesterol efflux regulation and triglycerides synthesis depending on the target gene and cellular type.