LARGE VERSUS SMALL UNILAMELLAR VESICLES MEDIATE REVERSE CHOLESTEROL TRANSPORT IN-VIVO INTO 2 DISTINCT HEPATIC METABOLIC POOLS - IMPLICATIONS FOR THE TREATMENT OF ATHEROSCLEROSIS

Phospholipid liposomes are synthetic mediators of ''reverse'' choleste rol transport from peripheral tissue to liver in vivo and can shrink a therosclerotic lesions in animals. Hepatic disposal of this cholestero l, however, has not been examined. We compared hepatic effects of larg e (approximate to 120-nm) and small (approximate to 35-nm) unilamellar vesicles (LUVs and SUVs), both of which mediate reverse cholesterol t ransport in vivo but were previously shown to be targeted to different cell types within the liver. On days 1, 3, and 5, rabbits were intrav enously injected with 300 mg phosphatidylcholine (LUVs or SUVs) per ki logram body weight or with the equivalent volume of saline. After each injection, LUV- and SUV-injected animals showed large increases in pl asma concentrations of unesterified cholesterol, indicating mobilizati on of tissue stores. After hepatic uptake of this cholesterol, however , SUV-treated animals developed persistently elevated plasma LDL conce ntrations, which by day 6 had increased to more than four times the va lues in saline-treated controls. In contrast, LUV-treated animals show ed normal LDL levels. By RNase protection assay, SUVs suppressed hepat ic LDL receptor mRNA at day 6 (to 61+/-4% of control, mean+/-SEM), whe reas LUVs caused a statistically insignificant stimulation. Hepatic HM G-CoA reductase message was also significantly suppressed with SUV, bu t not LUV treatment, and hepatic 7 alpha-hydroxylase message showed a similar trend. These data on hepatic mRNA levels indicate that SUVs, b ut not LUVs, substantially perturbed liver cholesterol homeostasis. We conclude that LUVs and SUVs mobilize peripheral tissue cholesterol an d deliver it to the liver, but to distinct metabolic pools that exert different regulatory effects. The effects of one of these artificial p articles, SUVs, suggest that reverse cholesterol transport may not alw ays be benign. In contrast, LUVs may be a suitable therapeutic agent, because they mobilize peripheral cholesterol to the liver without supp ressing hepatic LDL receptor mRNA and without provoking a subsequent r ise in plasma LDL levels.