Figure 2

LXR agonists increase ABCA1 and ABCG1 mRNA levels in rat peripheral blood cells. (A) Normal C57/Bl6 mice on normal chow were orally dosed with a single administration of 50 mg/kg LXR-623 (623) or vehicle (VEH). At 4 hours post-dosing, peripheral blood expression of ABCA1 and ABCG1 mRNA was quantified by real-time PCR, using GAPDH as the normalizer. The bars indicate the normalized mean transcript levels +/- SEM (n = 4 per group). (B) Male Long Evans rats were administered a single dose of 10 mg/kg T0901317 (T0), 30 mg/kg GW3965 (GW), 30 mg/kg LXR-623 (623) or vehicle (VEH) by oral gavage. Three hours later peripheral blood expression of ABCA1 and ABCG1 mRNA was quantified by real-time PCR (100 ng RNA/assay). All expression values were normalized for GAPDH mRNA, with the level of expression in rats treated with vehicle defined as 1.0. Values are the mean +/- SEM (n = 6 per group). (C) Male Long Evans rats were administered a single dose of vehicle (open circles) or 30 mg/kg LXR-623 (filled circles) by oral gavage. At the indicated time points plasma concentration of LXR-623 (uM) and peripheral blood cell expression of ABCA1 and ABCG1 were determined. Values are the mean +/- SEM (n = 6 per group). (D) Male Long Evans rats were administered a range (0.01 to 30 mg/kg) of GW3965 by oral gavage. Three hours later plasma GW3965 concentration, peripheral blood ABCA1 and ABCG1 expression, and spleen ABCA1 and ABCG1 expression were quantified. The induction of gene expression in the peripheral blood (open circles) and spleen (filled circles) is plotted as a function of the plasma drug concentration. The EC50 for GW3965 induction of ABCA1 expression in murine J774 macrophages is denoted for reference. Values are the mean +/- SEM (n = 6 per group). (E) As above, except that rats were treated with a range (1 to 30 mg/kg) of LXR-623. * p < 0.01 compared to vehicle treatment, as determined by Student's t test.