Abstract 1453: LXR-623, a novel Liver X Receptor modulator, displays neutral lipid effects in Cholesteryl Ester Transfer Protein-expressing species and inhibits atherosclerotic lesion progression in Low Density Lipoprotein receptor knockout mice
LXRα and LXRα are ligand-activated transcription factors involved in the upregulation of genes involved in reverse cholesterol transport (RCT), a process involved in cholesterol homeostasis. Unfortunately, synthetic LXR agonists also upregulate genes involved in lipogenesis. Therefore, the challenge is to identify molecules that will selectively upregulate genes involved in RCT with minimal effect on lipogenic genes. LXR-623 binds LXRα and LXRα with IC50 values of 24 and 179 nM respectively. In acLDL- loaded foam cell macrophages, LXR-623 upregulated ABCA1 mRNA and stimulated cholesterol efflux with EC50 values of 0.3–1.2 uM and displayed full efficacy as TO901317. While LXR agonists TO901317 and GW3965 increase the expression of SREBP1c that controls fatty acid and triglyceride (TG) biosynthesis, LXR-623 exhibits partial agonist activity for SREBP-1c mRNA induction and TG accumulation in HepG2 cells. LXR-623 was evaluated for its anti-atherosclerotic efficacy in high fat-fed LDLr k/o mice, a murine model of atherosclerosis. Mice were treated with 15 mg/kg LXR-623 or 10 mg/kg GW3965 for 8 weeks. At the end of the study, blood samples were collected for serum chemistry and aortic arches were removed for quantitative analysis of atherosclerotic lesion. Compared to high fat diet control mice, inclusion of GW3965 or LXR-623 resulted in a significant reduction of atherosclerotic lesion (28 and 37% for GW3965 and LXR-623, respectively) with no changes in serum chemistry. Similar observations were made when LXR-623 was administered by oral gavage (24% lesion reduction at 5mg/kg/day, the lowest dose tested). Since hamsters display lipoprotein metabolism that is closer to human lipoprotein metabolism, LXR-623 was evaluated in hamsters for its effects on serum cholesterol, TG and hepatic cholesterol and TG. Golden Syrian hamsters on normal diet were treated with different doses of LXR-623 (15–150 mg/kg/day by gavage) for 7 or 28 days. Compared to vehicle control, no changes were observed in serum or hepatic TG. While liver weights were increased at all doses tested (15, 50 and 120 mg/kg/day), hepatic cholesterol was significantly reduced at 120 mg/kg/day dose. These data distinguish LXR623 from the known LXR agonists.