Malovic Ivana, Sørensen Karen K, Elvevold Kjetil H, Nedredal Geir Ivar, Paulsen Steinar, Erofeev Alexander V, Smedsrød Bård H, McCourt Peter A G
Department of Cell Biology and Histology, University of Tromsø, NO-9037 Tromsø, Norway.
Hepatology. 2007 Jun;45(6):1454-61. doi: 10.1002/hep.21639.
The purpose of this study was to identify the receptor responsible for endocytosis of denatured collagen from blood. The major site of clearance of this material (at least 0.5 g/day in humans) is a receptor on liver sinusoidal endothelial cells (LSECs). We have now identified an 180-kDa endocytic receptor on LSECs, peptide mass fingerprinting of which revealed it to be the mannose receptor. Challenge of mannose-receptor knockout mice and their cultured LSECs revealed significantly reduced blood clearance and a complete absence of LSEC endocytosis of denatured collagen. Organ analysis of wild-type versus knockout mice after injection of denatured collagen revealed significantly reduced liver uptake in the knockout mice. Clearance/endocytosis of ligands for other receptors in these animals was as that for wild-type mice, and denatured collagen uptake in wild-type mice was not affected by other ligands of the mannose receptor, namely mannose and mannan. Furthermore, unlike that of mannose and mannan, endocytosis of denatured collagen by the mannose receptor is calcium independent. This suggests that the binding site for denatured collagen is distinct from that for mannose/mannan. Mannose receptors on LSECs appear to have less affinity for circulating triple helical type I collagen.
The mannose receptor is the main candidate for being the endocytic denatured collagen receptor on LSECs.
本研究的目的是确定负责从血液中内吞变性胶原蛋白的受体。这种物质（在人类中至少每天0.5克）清除的主要部位是肝窦内皮细胞（LSECs）上的一种受体。我们现已在LSECs上鉴定出一种180 kDa的内吞受体，其肽质量指纹图谱显示它是甘露糖受体。对甘露糖受体敲除小鼠及其培养的LSECs进行刺激，结果显示血液清除率显著降低，且变性胶原蛋白的LSEC内吞作用完全缺失。注射变性胶原蛋白后对野生型和敲除小鼠进行器官分析，结果显示敲除小鼠的肝脏摄取量显著降低。这些动物中其他受体配体的清除/内吞作用与野生型小鼠相同，野生型小鼠中变性胶原蛋白的摄取不受甘露糖受体的其他配体（即甘露糖和甘露聚糖）的影响。此外，与甘露糖和甘露聚糖不同，甘露糖受体对变性胶原蛋白的内吞作用不依赖于钙。这表明变性胶原蛋白的结合位点与甘露糖/甘露聚糖的结合位点不同。LSECs上的甘露糖受体对循环中的三螺旋I型胶原蛋白的亲和力似乎较低。
甘露糖受体是LSECs上内吞变性胶原蛋白受体的主要候选者。
