Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile.
Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile.
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DOI：
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发表时间：
1997-07
影响因子：
6.5
通讯作者：
D. Q. Wang;Beverly Paigen;Martin C. Carey
中科院分区：
文献类型：
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作者：
D. Q. Wang;Beverly Paigen;Martin C. Carey
LITS基因控制着近交系小鼠在含有高脂肪、高胆固醇和0.5%胆酸的致石饮食中形成胆固醇胆结石的敏感性。本研究明确了C57L、AKR和(C57L X AKR)F1小鼠胆汁在致石饲料饲养56天内的物理化学表型。我们发现，在所有C57L和F1小鼠中，胆固醇过饱和度增加，粘蛋白凝胶积累，更大的胆囊壁，以及雄性C57L和F1小鼠(80%)比雌性(40%)或AKR小鼠(15%)更频繁地形成胆结石。在雄性C57L和F1小鼠中，粘蛋白凝胶在3天后积累，随后是胆固醇过饱和和液晶、固体一水晶体的相分离，在43%的小鼠中，无水胆固醇晶体出现；而在雌性小鼠中，相分离延迟了2-9天，没有形成无水晶体。在AKR小鼠中，胆固醇过饱和和时相分离很少见且延迟，性别不影响表型。牛磺胆酸盐总是用与含有牛磺胆酸盐的模型胆汁体系相匹配的结晶序列取代内源性胆盐，尤其是牛磺酸-β-小鼠胆酸盐。我们的结论是：i)LITS基因决定了胆汁胆固醇过饱和、粘蛋白凝胶堆积、胆囊大小、时相分离和胆固醇结石的患病率。Ii)C57L和F1小鼠相同的表型表明，对胆固醇结石的易感性是遗传上的显性遗传，有利于雄性2：1。iii)AKR小鼠很少有粘蛋白凝胶积累、结晶和结石形成。这种成石的物理化学定义应该有助于进一步阐明Lith基因及其编码的蛋白质。
Lith genes control susceptibility to cholesterol gallstone formation in inbred strains of mice on a lithogenic diet containing high fat, high cholesterol and 0.5% cholic acid. Our study defines the physical-chemical phenotypes of C57L, AKR, and (C57L x AKR) F1 mouse gallbladder biles during 56 days on the lithogenic diet. We found enhanced cholesterol supersaturation, accumulation of mucin gel, and larger gallbladders in all C57L and F1 mice, as well as more frequent gallstone formation in male C57L and F1 mice (80%) compared to females (40%) or AKR mice (15%). In male C57L and F1 mice, mucin gel accumulated at 3 days, followed by cholesterol supersaturation and phase separation of liquid crystals, solid monohydrate crystals, and, in 43% of mice, anhydrous cholesterol crystals; whereas, in females, phase separations were delayed 2 to 9 days, and anhydrous crystals did not form. In AKR mice, cholesterol supersaturation and phase separations were infrequent and delayed, and gender did not influence the phenotype. Taurocholate invariably replaced endogenous bile salts, especially tauro-beta-muricholate, with crystallization sequences matching taurocholate-containing model bile systems. We conclude: i) Lith genes determine biliary cholesterol supersaturation, mucin gel accumulation, gallbladder size, phase-separation, and prevalence of cholesterol gallstones. ii) Identical phenotypes in C57L and F1 mice indicate susceptibility to cholesterol gallstones is genetically dominant, favoring males 2:1. iii) Mucin gel accumulation, crystallization, and stone formation are rare in AKR mice. This definition of the physical chemistry of lithogenesis should aid in further elucidation of the Lith genes and the proteins they encode.