Erranz Benjamín, Miquel Juan Francisco, Argraves W Scott, Barth Jeremy L, Pimentel Fernando, Marzolo María-Paz
Center for Cell Regulation and Pathology "Joaquin V. Luco", Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, and Instituto Milenio de Biología Fundamental y Aplicada, Santiago, Chile.
J Lipid Res. 2004 Dec;45(12):2185-98. doi: 10.1194/jlr.M400235-JLR200. Epub 2004 Sep 16.
Cholesterol crystal formation in the gallbladder is a key step in gallstone pathogenesis. Gallbladder epithelial cells might prevent luminal gallstone formation through a poorly understood cholesterol absorption process. Genetic studies in mice have highlighted potential gallstone susceptibility alleles, Lith genes, which include the gene for megalin. Megalin, in conjunction with the large peripheral membrane protein cubilin, mediates the endocytosis of numerous ligands, including HDL/apolipoprotein A-I (apoA-I). Although the bile contains apoA-I and several cholesterol-binding megalin ligands, the expression of megalin and cubilin in the gallbladder has not been investigated. Here, we show that both proteins are expressed by human and mouse gallbladder epithelia. In vitro studies using a megalin-expressing cell line showed that lithocholic acid strongly inhibits and cholic and chenodeoxycholic acids increase megalin expression. The effects of bile acids (BAs) were also demonstrated in vivo, analyzing gallbladder levels of megalin and cubilin from mice fed with different BAs. The BA effects could be mediated by the farnesoid X receptor, expressed in the gallbladder. Megalin protein was also strongly increased after feeding a lithogenic diet. These results indicate a physiological role for megalin and cubilin in the gallbladder and provide support for a role for megalin in gallstone pathogenesis.
胆囊中胆固醇晶体的形成是胆结石发病机制中的关键步骤。胆囊上皮细胞可能通过一个尚不清楚的胆固醇吸收过程来防止管腔内胆结石的形成。对小鼠的遗传学研究突出了潜在的胆结石易感等位基因，即Lith基因，其中包括巨膜蛋白基因。巨膜蛋白与外周大膜蛋白立方体细胞素共同作用，介导包括高密度脂蛋白/载脂蛋白A-I（apoA-I）在内的多种配体的内吞作用。尽管胆汁中含有apoA-I和几种与胆固醇结合的巨膜蛋白配体，但尚未对胆囊中巨膜蛋白和立方体细胞素的表达进行研究。在此，我们表明这两种蛋白均由人和小鼠的胆囊上皮细胞表达。使用表达巨膜蛋白的细胞系进行的体外研究表明，石胆酸强烈抑制，而胆酸和鹅去氧胆酸则增加巨膜蛋白的表达。通过分析喂食不同胆汁酸的小鼠胆囊中巨膜蛋白和立方体细胞素的水平，也在体内证实了胆汁酸（BAs）的作用。胆汁酸的作用可能由胆囊中表达的法尼醇X受体介导。喂食致石性饮食后，巨膜蛋白水平也显著升高。这些结果表明巨膜蛋白和立方体细胞素在胆囊中具有生理作用，并为巨膜蛋白在胆结石发病机制中的作用提供了支持。
