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Journal of Lipid Research, Vol. 45, 2185-2198, December 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

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^1,*

^* 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
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
Department of Cell Biology, Medical University of South Carolina, Charleston, SC
^** Departamento de Cirugía Digestiva, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

¹ To whom correspondence should be addressed. e-mail: mmarzolo{at}bio.puc.cl

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.

Abbreviations: ABC, ATP binding cassette; apoA-I, apolipoprotein A-I; BA, bile acid; CA, cholic acid; CDCA, chenodeoxycholic acid; CSI, cholesterol saturation index; FXR, farnesoid X receptor; GBE, gallbladder epithelium; GBEC, gallbladder epithelial cell; GST, glutathione S-transferase; LCA, lithocholic acid; NHE3, type 3 Na⁺/H⁺ exchanger; RAP, receptor-associated protein; RXR, retinoid X receptor; SR-BI, scavenger receptor class B type I; VDR, vitamin D receptor

Supplementary key words gallstone disease • apolipoprotein A-I • apolipoprotein J • farnesoid X receptor • vitamin D receptor • biliary cholesterol • gallbladder epithelial cells • Lith genes

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