Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats in vivo
Human recombinant apolipoprotein E redirects lipopolysaccharide from Kupffer cells to liver parenchymal cells in rats in vivo
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DOI：
10.1172/jci119427
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发表时间：
1997-05-15
影响因子：
15.9
通讯作者：
vanBerkel, TJC
中科院分区：
文献类型：
--
作者：
Rensen, PCN;vanOosten, M;vanBerkel, TJC
乳胶粒已被证明可以保护小鼠和大鼠免受致命剂量的脂多糖的伤害，并可能作为一种预防内毒素血症的治疗手段。然而，从人淋巴中分离的必要性阻碍了药物的应用，最近，我们从市售的脂类和重组人载脂蛋白E中开发了重组乳糜粒。本研究探讨了这些富含载脂蛋白E的乳剂将内毒素从Kupffer细胞重定向到肝实质细胞的有效性。在大鼠体内快速和特异性地结合肝脏(注射剂量的64.3%/-3.1%)和脾(4.1%/-0.7%)，脾对内毒素的摄取在与富载脂蛋白E或游离载脂蛋白E(P<；0.0001)孵育时减少了四到五倍，但不与单独的乳剂或脂褐素孵育。在肝脏内，I-125-内毒素主要与枯否细胞有关。富含apoE的乳剂或单独使用apoE可使Kupffer细胞摄取内毒素的能力降低8~9倍(P<；0.01)，肝实质细胞对Kupffer细胞的摄取比增加19.6倍，不含apoE的乳剂对内毒素的体内动力学无影响。脂多糖与重组乳胶粒的载脂蛋白E部分有选择性的相互作用。乳胶结合的游离载脂蛋白E结合了大约两个分子的内毒素，可能是通过其暴露的涉及精氨酸残基的亲水结构域。我们推测内源性乳糜粒对内毒素血症的保护作用可能与载脂蛋白E部分有关，而人重组载脂蛋白E可能是一种对内毒素血症有保护作用的药物。
Chylomicrons have been shown to protect mice and rats against a lethal dose of lipopolysaccharide and may serve as a therapeutic means to protect against endotoxemia. However, the requisite of isolation from human lymph hampers pharmaceutical application, Recently, we developed recombinant chylomicrons from commercially available lipids and human recombinant apolipoprotein E. The current study explored the effectiveness of these apoE-enriched emulsions in redirecting LPS from Kupffer cells to liver parenchymal cells. Upon injection into rats, I-125-LPS rapidly and specifically associated with the liver (64.3 +/- 3.1% of the injected dose) and spleen (4.1 +/- 0.7%), The uptake of LPS by the spleen was four- to fivefold reduced upon incubation with the apoE-enriched emulsion or free apoE (P < 0.0001), but not with emulsion alone or Lipofundin. Within the liver, I-125-LPS mainly associated with Kupffer cells. The uptake by Kupffer cells was eight- to ninefold reduced by the apoE-enriched emulsion or apoE alone (P < 0.01), and a 19.6-fold increased uptake ratio by liver parenchymal cells over Kupffer cells was observed, The emulsion without apoE had no effect on the in vivo kinetics of LPS. LPS interacted selectively with the apoE moiety of the recombinant chylomicron. Emulsion-associated and free apoE bound approximately two molecules of LPS, possibly by its exposed hydrophilic domain involving arginine residues. We anticipate that the protecting effect of endogenous chylomicrons against LPS-induced endotoxemia may result from the apoE moiety and that human recombinant apoE may serve as a therapeuticum to protect against endotoxemia.