Role of cholesterol crystallization-promoting protein in the pathogenesis of cholesterol gallstone.

胆汁中胆固醇的快速结晶是导致胆固醇胆结石形成的关键事件。近年来在胆结石患者的胆汁中发现了几种胆固醇结晶的糖蛋白启动子（免疫球蛋白、磷脂酶C、氨基肽酶N），引起了世界范围的关注。我们成功地分离出一个新的启动子，并鉴定为α _1-酸性糖蛋白。然而，没有研究比较这些体外启动子，它们在胆结石发病机制中的确切作用仍不清楚。因此，我们在本研究中旨在阐明这些胆固醇结晶促进剂在胆结石发病机制中的作用。首先，比较了这些糖蛋白在体外促进胆固醇结晶的活性。在胆汁中，只有α _1-酸性糖蛋白和免疫球蛋白在其生理水平上表现出促进活性。其次，采用新建立的特异性ELISA法检测不同胆结石和非胆结石患者胆汁中α _1-酸性糖蛋白水平，并与胆汁中胆固醇成核时间进行比较。结果表明，单独胆固醇结石和色素结石的胆汁中，α _1-酸性糖蛋白水平没有改变，但在多发性胆固醇结石的胆汁中，α _1-酸性糖蛋白水平特异性升高，其升高与成核时间的加快有关。胆α -酸糖蛋白在多发性胆固醇性胆结石的形成过程中起着重要的作用。

Rapid cholesterol crystallization in bile is the critical event leading to cholesterol gallstone formation. Several glycoprotein promoters (immunoglobulins, phospholipase C,aminopeptidase N) of cholesterol crystallization have recently been reported in bile with gallstones, which have received world-wide attention. We have successfully isolated a new promoter and identified it as alpha_1-acid glycoprotein. However, no study compared these promoters in vitro and their precise role in the pathogenesis of gallstones remains unknown. Therefore, we aimed in this study to clarify the role of these cholesterol crystallization-promoters in the pathogenesis of gallstones. Firstly, the cholesterol crystallization-promoting activity of these glycoproteins was compared in vitro. It was found that only alpha_1-acid glycoprotein and immunoglobulins exsert the promoting activity at their physiologic levels in bile. Secondly, the biliary levels of alpha_1-acid glycoprotein in various gallstone and non-gallstone patients were assayd by a newly established specific ELISA and compared with the cholesterol nucleation time in bile. This revealed that the alpha_1-acid glycoprotein level is not altered in biles with solitary cholesterol or pigment gallstones but it is specifically elevated in biles with multiple cholesterol gallstones and that its increase is associated with rapid nucleation time. The potent promoting activity in vitro as well as the specific increase in bile (in vivo) with multiple cholesterol gallstones suggest the critical role of the biliary alpha_1-acid glycoprotein in the formation of multiple cholesterol gallstones.