Rodrigueza W V, Mazany K D, Essenburg A D, Pape M E, Rea T J, Bisgaier C L, Williams K J
Department of Biochemistry, Medical College of Pennsylvania, Philadelphia, USA.
Arterioscler Thromb Vasc Biol. 1997 Oct;17(10):2132-9. doi: 10.1161/01.atv.17.10.2132.
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 (approximately equal to 120-nm) and small (approximately equal to 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 7 alpha-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.
磷脂脂质体是体内“逆向”胆固醇从外周组织转运至肝脏的合成介质，可使动物的动脉粥样硬化病变缩小。然而，尚未对肝脏对这种胆固醇的处理情况进行研究。我们比较了大（约120纳米）小（约35纳米）单层囊泡（LUVs和SUVs）对肝脏的影响，这两种囊泡在体内均介导逆向胆固醇转运，但先前显示它们靶向肝脏内不同的细胞类型。在第1、3和5天，给兔子静脉注射每千克体重300毫克磷脂酰胆碱（LUVs或SUVs）或等量体积的生理盐水。每次注射后，注射LUVs和SUVs的动物血浆中未酯化胆固醇浓度大幅升高，表明组织储存的胆固醇被动员起来。然而，在肝脏摄取这种胆固醇后，接受SUVs处理的动物血浆低密度脂蛋白（LDL）浓度持续升高，到第6天已增至生理盐水处理对照组的四倍多。相比之下，接受LUVs处理的动物LDL水平正常。通过核糖核酸酶保护试验，SUVs在第6天抑制肝脏LDL受体信使核糖核酸（mRNA）（降至对照组的61±4%，平均值±标准误），而LUVs引起的刺激在统计学上无显著意义。SUVs处理也显著抑制肝脏3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶信使，而LUVs处理则无此作用，肝脏7α-羟化酶信使也呈现类似趋势。这些关于肝脏mRNA水平的数据表明，SUVs而非LUVs会显著扰乱肝脏胆固醇稳态。我们得出结论，LUVs和SUVs可动员外周组织胆固醇并将其输送至肝脏，但进入不同的代谢池，产生不同的调节作用。这些人工颗粒之一SUVs的作用表明，逆向胆固醇转运可能并非总是有益的。相比之下，LUVs可能是一种合适的治疗剂，因为它们可将外周胆固醇动员至肝脏，而不抑制肝脏LDL受体mRNA，也不会引发随后血浆LDL水平的升高。
