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

胆汁中胆固醇快速结晶是导致胆固醇胆结石形成的关键事件。最近报道了胆结石胆汁中存在几种胆固醇结晶的糖蛋白促进剂（免疫球蛋白、磷脂酶C、氨肽酶N），引起了全世界的关注。我们成功分离出一个新的启动子，并将其鉴定为α_1-酸性糖蛋白。然而，没有研究在体外比较这些启动子，它们在胆结石发病机制中的确切作用仍然未知。因此，我们的研究目的是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，在体外比较了这些糖蛋白的胆固醇结晶促进活性。结果发现，只有α_1-酸性糖蛋白和免疫球蛋白在胆汁中的生理水平上发挥促进活性。其次，采用新建立的特异性ELISA法测定不同胆结石和非胆结石患者胆汁中α_1酸性糖蛋白的水平，并与胆汁中胆固醇成核时间进行比较。这表明，在具有单一胆固醇或胆色素结石的胆汁中，α_1-酸性糖蛋白水平没有改变，但在具有多个胆固醇胆结石的胆汁中，α_1-酸性糖蛋白水平特别升高，并且其增加与快速成核时间相关。体外有效的促进活性以及多发性胆固醇胆结石时胆汁（体内）的特异性增加表明胆汁α_1-酸性糖蛋白在多发性胆固醇胆结石形成中的关键作用。

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.