Bonet B, Chait A, Gown A M, Knopp R H
Northwest Lipid Research Clinic, University of Washington School of Medicine, Seattle 98104, USA.
Atherosclerosis. 1995 Jan 20;112(2):125-36. doi: 10.1016/0021-9150(94)05404-7.
All major classes of normal circulating lipoproteins can be metabolized by human placental cells. However, the metabolism of abnormal or modified lipoproteins has been little studied. We therefore investigated whether placental cells metabolize acetylated low density lipoprotein (ac-LDL) or oxidatively-modified LDL (ox-LDL), both of which are metabolized by scavenger receptors, and if so, whether modified LDL stimulates progesterone secretion as does normal LDL. Placental macrophages and trophoblasts were isolated on a 40% Percoll gradient after enzymatic digestion. The cellular uptake and degradation of [125I]-ac-LDL was 20-fold higher than [125I]-LDL in both macrophages and trophoblasts. Both cell types demonstrated high affinity and saturable degradation. Similarly, increased esterification of [14C]-labelled oleic acid to cholesterol was observed when cells were incubated with ac-LDL vs. LDL. Uptake of ac-LDL by trophoblasts also was demonstrated by colocalization of fluorescently labelled ac-LDL and fluorescent antibodies specific for trophoblasts. Similar colocalization of fluorescent ac-LDL and fluorescent anti-macrophage specific epitopes was seen in macrophages. Uptake and degradation of [125I]-ac-LDL by placental cells was inhibited by increasing concentrations of unlabelled ac-LDL or fucoidin but not LDL, indicating uptake by a scavenger receptor. Both unlabelled ac-LDL and ox-LDL inhibited uptake of [125I]-labelled ox-LDL, suggesting uptake by a common mechanism. Although secretion of progesterone by trophoblasts was stimulated by incubation with LDL, progesterone secretion by trophoblasts was not stimulated by ac-LDL and only minimally stimulated by ox-LDL.
Scavenger receptors are present in human placental trophoblasts as well as macrophages. Scavenger receptor activity greatly exceeds that of LDL receptor activity in both cell types. However, cholesterol assimilated via the scavenger receptor pathway appears to be disconnected from endocrine steroidogenesis in trophoblasts. Thus, we hypothesize that scavenger receptors function in trophoblasts to degrade modified lipoproteins and prevent toxic effects on placental cellular function and fetal growth and development.
正常循环脂蛋白的所有主要类别均可被人胎盘细胞代谢。然而，异常或修饰脂蛋白的代谢研究较少。因此，我们研究了胎盘细胞是否代谢乙酰化低密度脂蛋白（ac-LDL）或氧化修饰的LDL（ox-LDL），这两种脂蛋白均由清道夫受体代谢，以及如果是这样，修饰的LDL是否像正常LDL一样刺激孕酮分泌。酶消化后，通过40%的Percoll梯度分离胎盘巨噬细胞和滋养层细胞。在巨噬细胞和滋养层细胞中，[125I]-ac-LDL的细胞摄取和降解比[125I]-LDL高20倍。两种细胞类型均表现出高亲和力和饱和降解。同样，当细胞与ac-LDL而非LDL孵育时，观察到[14C]标记的油酸向胆固醇的酯化增加。滋养层细胞对ac-LDL的摄取也通过荧光标记的ac-LDL与滋养层细胞特异性荧光抗体的共定位得到证实。在巨噬细胞中也观察到荧光ac-LDL与荧光抗巨噬细胞特异性表位的类似共定位。胎盘细胞对[125I]-ac-LDL的摄取和降解受到未标记的ac-LDL或岩藻糖胶浓度增加的抑制，但不受LDL的抑制，表明通过清道夫受体摄取。未标记的ac-LDL和ox-LDL均抑制[125I]标记ox-LDL的摄取，提示通过共同机制摄取。虽然与LDL孵育可刺激滋养层细胞分泌孕酮，但ac-LDL不刺激滋养层细胞分泌孕酮，ox-LDL仅轻微刺激。
人胎盘滋养层细胞和巨噬细胞中存在清道夫受体。在两种细胞类型中，清道夫受体活性大大超过LDL受体活性。然而，通过清道夫受体途径同化的胆固醇似乎与滋养层细胞中的内分泌类固醇生成无关。因此，我们假设清道夫受体在滋养层细胞中发挥作用，降解修饰的脂蛋白，并防止对胎盘细胞功能以及胎儿生长发育产生毒性作用。
