Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.
Low density lipoprotein receptor-independent hepatic uptake of a synthetic, cholesterol-scavenging lipoprotein: implications for the treatment of receptor-deficient atherosclerosis.
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低密度脂蛋白受体独立的肝脏对合成的胆固醇清除脂蛋白的摄取：对治疗受体缺陷型动脉粥样硬化的影响。
DOI：
10.1073/pnas.85.1.242
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发表时间：
1988
影响因子：
11.1
通讯作者：
Goldsmith,SJ
中科院分区：
文献类型：
--
作者：
Williams,KJ;Vallabhajosula,S;Rahman,IU;Donnelly,TM;Parker,TS;Weinrauch,M;Goldsmith,SJ
本文研究了注入的111 In标记磷脂脂质体在缺乏低密度脂蛋白（LDL）受体的Watanabe遗传性高脂血症（WHHL）家兔和正常对照家兔中的代谢。WHHL中111 In和过量磷脂从血浆中清除的半衰期（t1/2）分别为20.8 +/- 0.9 h和20.3 +/- 4.6 h，正常家兔中分别为20.0 +/- 0.8 h和19.6 +/- 2.2 h（平均值+/- SEM; n = 4）。到输注后6小时，WHHL中未酯化胆固醇的血浆浓度增加了2.2 +/- 0.23 mmol/L，正常家兔中增加了2.1 +/- 0.04 mmol/L，可能反映了组织储存的动员。到输注后70小时，两组家兔中过量血浆胆固醇的消失率均超过90%。通过定量伽马照相机成像，两组之间111 In标记的脂质体随时间推移的肝捕获无法区分。尸检时，肝脏是主要的清除器官，获得22.0% +/- 1.7%（WHHL）和16.8% +/- 1.0%（总111 In正常值）。主动脉摄取111 In小于0.02%。因此，胆固醇的动员和磷脂脂质体的肝摄取不需要LDL受体。由于磷脂输注在遗传正常的动物中产生动脉粥样硬化的快速实质性消退，我们的结果表明磷脂脂质体或甘油三酯磷脂乳剂（例如，在WHHL兔和家族性高胆固醇血症的人中，胰岛素）可能减少动脉粥样硬化。
The metabolism of infused 111In-labeled phospholipid liposomes was examined in Watanabe heritable hyperlipidemic (WHHL) rabbits, which lack low density lipoprotein (LDL) receptors, and in normal control rabbits. The half-times (t1/2) for clearance of 111In and excess phospholipid from plasma were 20.8 +/- 0.9 hr and 20.3 +/- 4.6 hr in WHHL and 20.0 +/- 0.8 hr and 19.6 +/- 2.2 hr in the normal rabbits (means +/- SEM; n = 4). By 6 hr postinfusion, the plasma concentration of unesterified cholesterol increased by 2.2 +/- 0.23 mmol/liter in WHHL and 2.1 +/- 0.04 mmol/liter in normal rabbits, presumably reflecting mobilization of tissue stores. Disappearance of excess plasma cholesterol was greater than 90% complete in both groups of rabbits by 70 hr postinfusion. By quantitative gamma camera imaging, hepatic trapping of 111In-labeled liposomes over time was indistinguishable between the two groups. At autopsy, the liver was the major organ of clearance, acquiring 22.0% +/- 1.7% (WHHL) and 16.8% +/- 1.0% (normal of total 111In. Aortic uptake of 111In was less than 0.02%. Thus, mobilization of cholesterol and hepatic uptake of phospholipid liposomes do not require LDL receptors. Because phospholipid infusions produce rapid substantial regression of atherosclerosis in genetically normal animals, our results suggest that phospholipid liposomes or triglyceride phospholipid emulsions (e.g., Intralipid) might reduce atherosclerosis in WHHL rabbits and in humans with familial hypercholesterolemia.