Abstract 1101: Liver X Receptor Activation Promotes Macrophage-to-Feces Reverse Cholesterol Transport in a Dyslipidemic Hamster Model
Objectives- Liver-X-receptor (LXR) activation promotes reverse cholesterol transport (RCT) in rodents but concerns remain regarding side effects (e.g. higher triglycerides and LDL-c levels) in species expressing cholesteryl ester transfer protein (CETP). In the face of dyslipidemia, it is also unclear whether LXR activation stimulates macrophage-to-feces RCT in CETP-species. Among these species, hamster is known to have a more human-like lipoprotein metabolism. We therefore used a hamster model with both dyslipidemia and liver steatosis to investigate the effects of LXR activation on RCT in vivo.
Methods- Golden Syrian hamsters were made dyslipidemic with a chow+0.3% cholesterol diet provided ad libitum over 4 weeks. Hamsters were then treated with vehicle or LXR agonist GW3965 (30mg/kg bid) over 10 days. To investigate RCT, radiolabeled 3H-cholesterol macrophages or 3H-cholesteryl oleate-HDL were then injected to measure plasma and feces radioactivity over 72 or 48 hours, respectively.
Results- Cholesterol-enriched diet increased VLDL-triglycerides and total cholesterol levels in all lipoprotein fractions, as measured by fast protein liquid chromatography (FPLC). This diet also increased liver cholesterol and triglycerides by 535% and 168%, respectively (p<0.001 vs. chow-fed hamsters). Overall, treatment with GW3965 failed to significantly improve both dyslipidemia and liver steatosis. However, mRNA expression of ABCA1, G5 and G8 was strongly increased in both liver and intestine (p<0.001 vs. vehicle), while NPC1L1 expression was 34% lower (p<0.02). After 3H-cholesterol labeled macrophages injection, GW3965 treatment significantly increased the 3H-tracer appearance by 30% in plasma over 72 hours, while fecal 3H-cholesterol excretion increased by 156% (p<0.001). After 3H-cholesteryl oleate-HDL injection, GW3965 increased HDL-derived cholesterol fecal excretion by 64% (p<0.01 vs. vehicle), while HDL-cholesteryl esters fractional catabolic rate remained unchanged.
Conclusion- Despite no beneficial effect on lipid levels, LXR activation promotes macrophage-to-feces RCT in dyslipidemic hamsters. These results emphasize the use of species with a more human-like lipoprotein metabolism for pre-clinical drug profiling.