J. Lipid Res.
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A more recent version of this article appeared on December 1, 2004

Papers In Press, published online ahead of print September 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400235-JLR200
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Submitted on June 17, 2004
Revised on September 2, 2004
Accepted on September 14, 2004

Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids

Benjamín Erranz, Juan Francisco Miquel, W. Scott Argraves, Jeremy L. Barth, Fernando Pimentel, and María-Paz Marzolo

Cell and Molecular Biology, Pontificia Universidad Católica de Chile, Santiago, RM 6513492

Corresponding Author: mmarzolo{at}bio.puc.cl

Cholesterol hypersecretion by the liver and cholesterol crystal formation in the gallbladder are key steps in gallstone pathogenesis. Cholesterol absorption by gallbladder epithelial cells (GBEC) might prevent cholesterol crystallization and gallstone formation in gallbladder lumen. However the cellular mechanisms involved in cholesterol uptake and trafficking in GBEC are poorly understood. Genetic studies in mice have highlighted potential gallstone susceptibility alleles, Lith genes. The gene for megalin, an endocytic receptor belonging to the LDL-receptor family is a candidate Lith gene. Megalin works in conjunction with cubilin, a large peripheral membrane protein, to mediate endocytosis of numerous ligands including HDL/apoA-I. Despite the fact that megalin is a candidate Lith gene and that bile contains apoA-I and other cholesterol-binding megalin ligands, the expression of megalin in the gallbladder has not been investigated. Here we show that megalin and cubilin are expressed by human and mouse gallbladder epithelia. In vitro studies using the megalin expressing cell line LLC-PK1, shown that lithocholic acid (LCA) strongly inhibits and cholic (CA) and chenodeoxycholic (CDCA) increase megalin expression. The effects of bile acids (BAs) were also demonstrated in vivo, analysing gallbladder levels of megalin and cubilin from mice fed with different BAs. The BAs effects could be mediated by the transcription factor, farnesoid X receptor (FXR), which was expressed in gallbladder. Megalin but not cubilin was also strongly upregulated after feeding a lithogenic diet. In conclusion, these results indicate a physiological role for megalin and cubilin in the gallbladder and also provide support for a role for megalin in gallstone pathogenesis.


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