CHOLESTENOIC ACID ANALOG (27-NORCHOLESTENOIC) EFFECTS OVER LIVER X RECEPTOR (LXR) ACTIVITY

NAVALESI DANIELA; GRINMAN DIEGO; DANSEY VIRGINIA; PECCI ADALI

San Carlos de Bariloche

Simposio; SISTAM 2015; 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 the mammary gland, LXRs not only regulate milk lipid synthesis and secretion during lactation but have antiproliferative and proapoptotic effects over epithelial cells. Numerous evidences link thes effects with LXR activity as a lipid homeostasis modulator. Our goal was to analyze the actions of the novel ligand 27-norcholestenoic (27-norchol), a cholestenoic acid analog, over 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 GW3965, a commercial synthetic LXR agonist, incubated over 18 hs induced SREBP1 (sterol regulatory element-binding protein 1) expression 2.36 ± 0.58 fold over 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. Moreover, 27-norchol alone inhibited FAS expression 0.66 ± 0.14 fold over control, stimulated ApoE expression 1.5 ± 0.20 and ABCA1 1.56 ± 0.34 fold, and did not modify SREBP1 expression. At the same time, 27-norchol acted as an antagonist and invert 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.