Stefulj Jasminka, Panzenboeck Ute, Becker Tatjana, Hirschmugl Birgit, Schweinzer Cornelia, Lang Ingrid, Marsche Gunther, Sadjak Anton, Lang Uwe, Desoye Gernot, Wadsack Christian
Institute of Pathophysiology and Immunology, Center of Molecular Medicine, Medical University Graz, Graz, Austria.
Circ Res. 2009 Mar 13;104(5):600-8. doi: 10.1161/CIRCRESAHA.108.185066. Epub 2009 Jan 22.
Although maternal-fetal cholesterol transfer may serve to compensate for insufficient fetal cholesterol biosynthesis under pathological conditions, it may have detrimental consequences under conditions of maternal hypercholesterolemia leading to preatherosclerotic lesion development in fetal aortas. Maternal cholesterol may enter fetal circulation by traversing syncytiotrophoblast and endothelial layers of the placenta. We hypothesized that endothelial cells (ECs) of the fetoplacental vasculature display a high and tightly regulated capacity for cholesterol release. Using ECs isolated from human term placenta (HPECs), we investigated cholesterol release capacity and examined transporters involved in cholesterol efflux pathways controlled by liver-X-receptors (LXRs). HPECs demonstrated 2.5-fold higher cholesterol release to lipid-free apolipoprotein (apo)A-I than human umbilical vein ECs (HUVECs), whereas both cell types showed similar cholesterol efflux to high-density lipoproteins (HDLs). Interestingly, treatment of HPECs with LXR activators increased cholesterol efflux to both types of acceptors, whereas no such response could be observed for HUVECs. In line with enhanced cholesterol efflux, LXR activation in HPECs increased expression of ATP-binding cassette transporters ABCA1 and ABCG1, while not altering expression of ABCG4 and scavenger receptor class B type I (SR-BI). Inhibition of ABCA1 or silencing of ABCG1 decreased cholesterol efflux to apoA-I (-70%) and HDL(3) (-57%), respectively. Immunohistochemistry localized both transporters predominantly to the apical membranes of placental ECs in situ. Thus, ECs of human term placenta exhibit unique, efficient and LXR-regulated cholesterol efflux mechanisms. We propose a sequential pathway mediated by ABCA1 and ABCG1, respectively, by which HPECs participate in forming mature HDL in the fetal blood.
尽管母胎胆固醇转运可能在病理条件下有助于补偿胎儿胆固醇生物合成不足，但在母体高胆固醇血症的情况下，它可能会产生有害后果，导致胎儿主动脉出现动脉粥样硬化前期病变。母体胆固醇可通过穿过胎盘的合体滋养层和内皮细胞层进入胎儿循环。我们推测，胎儿胎盘血管系统的内皮细胞（ECs）具有高度且严格调控的胆固醇释放能力。我们使用从足月人胎盘分离的内皮细胞（HPECs），研究了胆固醇释放能力，并检测了参与由肝X受体（LXRs）控制的胆固醇流出途径的转运蛋白。与人类脐静脉内皮细胞（HUVECs）相比，HPECs向无脂载脂蛋白（apo）A-I释放的胆固醇高出2.5倍，而两种细胞类型向高密度脂蛋白（HDLs）的胆固醇流出量相似。有趣的是，用LXR激活剂处理HPECs会增加向两种类型受体的胆固醇流出，而HUVECs未观察到这种反应。与胆固醇流出增强一致，HPECs中LXR激活增加了ATP结合盒转运蛋白ABCA1和ABCG1的表达，而未改变ABCG4和B类I型清道夫受体（SR-BI）的表达。抑制ABCA1或沉默ABCG1分别使向apoA-I（-70%）和HDL(3)（-57%）的胆固醇流出减少。免疫组织化学将这两种转运蛋白主要定位在原位胎盘内皮细胞的顶端膜上。因此，足月人胎盘的内皮细胞表现出独特、高效且受LXR调节的胆固醇流出机制。我们提出了分别由ABCA1和ABCG1介导的顺序途径，通过该途径HPECs参与在胎儿血液中形成成熟的HDL。
