The liver X receptors α and β (LXR) are responsible for transcriptional regulation of a number of genes involved in cholesterol efflux from cells and therefore may be molecular target for the treatment of cardiovascular disease. However, the effects of LXR ligands on cholesterol turnover in cells and in animals have not been examined comprehensively. Here we examined the effects of LXR agonists on cholesterol handling in both in-vitro (HepG2 cells) and in-vivo (Golden Syrian hamsters) models using stable isotope probes and corresponding multi-compartmental mathematical modeling. A two compartmental analysis of 1-13C sodium acetate tracer in combination with Mass Isotopomer Distribution Analysis (MIDA) revealed varying responses to cholesterol handling (e.g. synthesis, catabolism, influx and efflux) in cultured HepG2 cells following treatment with synthetic non-steroidal LXR agonists (GW3965, T0901317, SB742881) and steroidal LXR agonists (22(R)-hydroxycholesterol, 24(S),25-epoxycholesterol, Dimethyl-3β-hydroxy-cholenamide). Unlike the steroidal LXR agonists, non-steroidal LXR agonists increased cholesterol synthesis by 5 fold, decreased cholesterol influx by 70-80% and increased cholesterol efflux by 2 fold. For experiments assessing LXR effects on cholesterol handling in hamsters, six compartmental model was created to define free cholesterol and esterified cholesterol flux in three separate pools (plasma, liver, extrahepatic tissue). The six compartmental analysis of 3,4-13C cholesterol tracer in hamsters resulted in a slight, but non-significant increase in free cholesterol efflux from liver (60%) following treatment with LXR agonist: GW3965, consistent with in vitro observations. In summary, comprehensive mathematical models were developed in order to assess cholesterol handling in cells and in animals. For the first time, LXR perturbation of cholesterol handling in these in vivo systems was assessed.Ph.D., Physics -- Drexel University, 200
