Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids.
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.
Erranz
Benjamín
B
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.
Miquel
Juan Francisco
JF
Argraves
W Scott
WS
Barth
Jeremy L
JL
Pimentel
Fernando
F
Marzolo
María-Paz
MP
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D051152:Clusterin; D004285:Dogs; D004848:Epithelium / Q000378:metabolism; D005704:Gallbladder / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D026561:Low Density Lipoprotein Receptor-Related Protein-2 / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D051379:Mice; D008806:Mice, Inbred AKR; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018832:Molecular Chaperones / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics*
D001647:Bile Acids and Salts; C495242:CLU protein, human; C495243:Clu protein, mouse; D051152:Clusterin; D006023:Glycoproteins; D026561:Low Density Lipoprotein Receptor-Related Protein-2; D018832:Molecular Chaperones; D011956:Receptors, Cell Surface; C029486:intrinsic factor-cobalamin receptor