ROLE OF GALLBLADDER MUCUS HYPER-SECRETION IN THE EVOLUTION OF CHOLESTEROL GALLSTONES - STUDIES IN THE PRAIRIE DOG
ROLE OF GALLBLADDER MUCUS HYPER-SECRETION IN THE EVOLUTION OF CHOLESTEROL GALLSTONES - STUDIES IN THE PRAIRIE DOG
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DOI：
10.1172/jci110209
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发表时间：
1981-01-01
影响因子：
15.9
通讯作者：
CAREY, MC
中科院分区：
文献类型：
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作者：
LEE, SP;LAMONT, JT;CAREY, MC
粘蛋白糖蛋白可能在胆结石的病理生理学中起重要作用。研究了饲喂胆固醇的草原犬胆汁脂质、胆汁粘蛋白分泌与胆结石形成的关系。对胆囊外植体的器官培养研究表明，饲喂后3、5、8和14d，[~3H]氨基葡萄糖掺入组织和分泌型胆囊糖蛋白的量显著增加。在Sepharose4B上对分泌的糖蛋白进行凝胶过滤表明，大部分放射性存在于一个100万mW的大分子中。胆粘蛋白分泌的增加是器官特异性的，因为[~3H]-氨基葡萄糖掺入胃和结肠的糖蛋白不受胆固醇喂养的影响。[~3H]甘露糖掺入胆囊膜糖蛋白不受胆固醇摄取的影响。停止胆固醇饮食和结扎胆囊管后，糖蛋白合成和分泌速度恢复正常，防止了胆囊粘蛋白的高分泌。对粘蛋白分泌的刺激作用显然是胆汁的一种成分。5d后，胆汁中的胆固醇以胶束、液晶和晶体形式存在，而肝胆汁在喂饲胆固醇的整个过程中仍保持单一胶束状态。比较匀浆和离心法测定的胆汁胆固醇饱和度指数。在第5天和第8天，胆汁胶束相的饱和度略低于匀浆胆汁，这反映了胆固醇在胆汁中的持续成核。纯化的人胆囊粘蛋白凝胶诱导过饱和肝胆汁中卵磷脂-胆固醇液晶的成核。对照过饱和的肝胆汁不能因添加其他蛋白质而成核，放置数天后仍保持稳定。饲喂胆固醇的草原犬胆汁中胆固醇含量的增加明显刺激了胆汁粘液的高分泌。胆囊粘液凝胶显然是胆汁胆固醇的成核剂。
Mucin glycoproteins may be important in the pathophysiology of gallstones. The relationship among biliary lipids, gallbladder mucin secretion and gallstone formation in cholesterol-fed prairie dogs [Cynomys ludovicianus], were studied. Organ culture studies of gallbladder explants revealed that the incorporation of [3H]glucosamine into tissue and secretory gallbladder glycoproteins was significantly increased at 3, 5, 8 and 14 d [day] of feeding. Gel filtration of the secreted glycoprotein on Sepharose 4B indicated that the majority of radioactivity was present in a macromolecule of > 1 million MW. The increased secretion of gallbladder mucin was organ specific, in that [3H]-glucosamine incorporation into glycoproteins of stomach and colon was unaffected by cholesterol feeding. The incorporation of [3H]mannose into gallbladder membrane glycoproteins was not altered by cholesterol feeding. The rate of glycoprotein synthesis and secretion returned to normal upon withdrawal of the cholesterol diet and ligation of the cystic duct before cholesterol feeding prevented gallbladder mucin hypersecretion. The stimulus to mucin secretion was evidently a constituent of bile. Gallbladder bile after 5 d contained cholesterol in micelles, liquid crystals and crystals, whereas hepatic bile remained a single micellar phase throughout cholesterol feeding. The cholesterol-saturation indices of gallbladder bile were compared in homogenized and centrifuged samples. The micellar phase of gallbladder bile was appreciably less saturated than homogenized bile at 5 and 8 d, which reflects the continuous nucleation of cholesterol in the gallbladder. Purified human gallbladder mucin gels induced nucleation of lecithin-cholesterol liquid crystals from supersaturated hepatic bile. These in turn gave rise to cholesterol monohydrate crystals within 18 h. Control supersaturated hepatic bile could not be nucleated by the addition of other proteins and was stable for days upon standing. The increase in cholesterol content of bile in cholesterol-fed prairie dogs apparently stimulates gallbladder mucus hypersecretion. Gallbladder mucus gel is apparently a nucleating agent for biliary cholesterol.