Rensen P C, Herijgers N, Netscher M H, Meskers S C, van Eck M, van Berkel T J
Division of Biopharmaceutics, Leiden-Amsterdam Center for Drug Research, University of Leiden, Sylvius Laboratories, The Netherlands.
J Lipid Res. 1997 Jun;38(6):1070-84.
Apolipoprotein E (apoE) is an important determinant for the uptake of triglyceride-rich emulsions and lipoproteins by the liver, and exerts affinity for both the LDL receptor (LDLr) and a distinct liver-specific recognition site. Our current aim was to assess the mechanism underlying the receptor-specificity of apoE-carrying lipoproteins. Triglyceride-rich emulsions were synthesized, with mean sizes of 50, 80, and 150 nm. These fractions efficiently acquired apoE from rat serum, and were processed by LPL in vivo with a similar efficiency. Upon injection of the [5H]cholesteryl oleate-labeled emulsions into rats, the liver association rate was positively correlated with particle size (24 +/- 2%, 54 +/- 1%, and 64 +/- 3% of the injected dose at 20 min after injection, respectively) and the liver uptake was predominantly exerted by parenchymal cells. The role of the LDLr in emulsion clearance was established in wild-type versus LDLr knockout mice. In the absence of the LDLr, an 8-fold increased serum half-life was observed for the small emulsion, concomitant with a 6- and 15-fold decreased uptake by the liver and adrenals at 60 min after injection, respectively. In contrast, the in vivo behavior of the large emulsion was independent of the LDLr. Both the ratio of apoE:C on the emulsions upon serum incubation and the alpha-helical content of apoE were inversely correlated with particle size, indicating that these factors may be involved in the emulsion size-dependent receptor specificity in vivo. It is concluded that the contribution of the LDLr to the apoE-mediated clearance of emulsions by the liver and adrenals strongly increases with decreasing particle size, while large particles initially associate with a distinct liver-specific recognition site. As these emulsions mimic chylomicrons, we anticipate that the apoE-dependent metabolic behavior of chylomicrons (remnants) is largely dependent on their size.
载脂蛋白E（apoE）是肝脏摄取富含甘油三酯的乳剂和脂蛋白的重要决定因素，对低密度脂蛋白受体（LDLr）和一个独特的肝脏特异性识别位点均具有亲和力。我们当前的目标是评估携带apoE的脂蛋白受体特异性的潜在机制。合成了平均粒径为50、80和150 nm的富含甘油三酯的乳剂。这些组分有效地从大鼠血清中获取apoE，并在体内被脂蛋白脂肪酶（LPL）以相似的效率进行处理。将[5H]胆固醇油酸酯标记的乳剂注射到大鼠体内后，肝脏结合率与颗粒大小呈正相关（注射后20分钟时，分别为注射剂量的24±2%、54±1%和64±3%），并且肝脏摄取主要由实质细胞完成。在野生型小鼠与LDLr基因敲除小鼠中确定了LDLr在乳剂清除中的作用。在缺乏LDLr的情况下，观察到小乳剂的血清半衰期增加了8倍，同时注射后60分钟时肝脏和肾上腺的摄取分别减少了6倍和15倍。相比之下，大乳剂的体内行为与LDLr无关。血清孵育后乳剂上apoE与C的比例以及apoE的α-螺旋含量均与颗粒大小呈负相关，表明这些因素可能参与了体内乳剂大小依赖性的受体特异性。结论是，LDLr对肝脏和肾上腺通过apoE介导的乳剂清除的贡献随着颗粒大小的减小而显著增加，而大颗粒最初与一个独特的肝脏特异性识别位点结合。由于这些乳剂模拟乳糜微粒，我们预计乳糜微粒（残粒）依赖apoE的代谢行为在很大程度上取决于它们的大小。
