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Abstract Phospholipid liposomes are synthetic mediators of “reverse” cholesterol transport from peripheral tissue to liver in vivo and can shrink atherosclerotic lesions in animals. Hepatic disposal of this cholesterol, however, has not been examined. We compared hepatic effects of large (≈120-nm) and small (≈35-nm) unilamellar vesicles (LUVs and SUVs), both of which mediate reverse cholesterol transport in vivo but were previously shown to be targeted to different cell types within the liver. On days 1, 3, and 5, rabbits were intravenously injected with 300 mg phosphatidylcholine (LUVs or SUVs) per kilogram body weight or with the equivalent volume of saline. After each injection, LUV- and SUV-injected animals showed large increases in plasma concentrations of unesterified cholesterol, indicating mobilization of tissue stores. After hepatic uptake of this cholesterol, however, SUV-treated animals developed persistently elevated plasma LDL concentrations, which by day 6 had increased to more than four times the values in saline-treated controls. In contrast, LUV-treated animals showed normal LDL levels. By RNase protection assay, SUVs suppressed hepatic LDL receptor mRNA at day 6 (to 61±4% of control, mean±SEM), whereas LUVs caused a statistically insignificant stimulation. Hepatic HMG-CoA reductase message was also significantly suppressed with SUV, but not LUV treatment, and hepatic 7α-hydroxylase message showed a similar trend. These data on hepatic mRNA levels indicate that SUVs, but not LUVs, substantially perturbed liver cholesterol homeostasis. We conclude that LUVs and SUVs mobilize peripheral tissue cholesterol and deliver it to the liver, but to distinct metabolic pools that exert different regulatory effects. The effects of one of these artificial particles, SUVs, suggest that reverse cholesterol transport may not always be benign. In contrast, LUVs may be a suitable therapeutic agent, because they mobilize peripheral cholesterol to the liver without suppressing hepatic LDL receptor mRNA and without provoking a subsequent rise in plasma LDL levels.