Abstract
Although the role of cholesterol absorption by the gallbladder epithelium in gallstone formation is well established, the exact process is poorly understood. Potential candidates for regulation of transepithelial cholesterol transport are suggested to be two large membrane multiple ligand receptors, megalin and cubilin. We studied the expression of these two proteins in both acalculous and calculous human gallbladder epithelia. Adult human gallbladder tissues were received from 21 patients (9 men, 12 women) who had undergone cholecystectomy. The patients were divided into two groups: group A (calculous gallbladder group; 5 men, 6 women; mean age 64.4 ± 11.1 years) with cholelithiasis, and group B (acalculous gallbladder group; 4 men, 6 women; mean age 55.3 ± 16.1 years). In the gallbladder tissues megalin and cubilin expression was studied by immunohistochemistry and conventional RT-PCR, and gene expression levels were estimated by real-time RT-PCR. Both megalin and cubilin gene transcripts were found in total RNA preparations from acalculous gallbladder. In contrast, in preparations from calculous gallbladder, none or only one of the proteins was detected. Immunoreactive proteins were detected in the simple columnar acalculous gallbladder epithelium but not in the calculous gallbladder epithelium. Our results show different expression patterns of the two proteins in calculous gallbladders and acalculous gallbladders. In the latter both proteins are expressed, suggesting an association with gallstone formation and implying a putative role of the two proteins in cholesterol endocytosis. In other words, the presence of both proteins may be essential for the prevention of stone formation.
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References
Portincasa P, Moschetta A, Palasciano G (2006) Cholesterol gallstone disease. Lancet 368:230–239
Erranz B, Miquel JF, Argraves WS et al (2004) Megalin and cubilin expression in gallbladder epithelium and regulation by bile acids. J Lipid Res 5:2185–2198
Dowling RH (2000) Review: pathogenesis of gallstones. Aliment Pharmacol Ther 14[Suppl 2]:39–47
Mittal B, Mittal R (2002) Genetics of gallstone disease. J Postgrad Med 48:149–152
Wang DQ-H, Lammert F, Paigen B, Carey MC (1999) Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: pathophysiology of biliary secretion. J Lipid Res 40:2066–2079
Lammert F, Wang DQ-H, Paigen B, Carey MC (1999) Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: integrated activities of hepatic lipid regulatory enzymes. J Lipid Res 40:2080–2090
Lyons MA, Wittenburg H, Li R et al (2003) New quantitative trait loci that contribute to cholesterol gallstone formation detected in an intercross of CAST/Ei and 129S1/SvImJ inbred mice. Physiol Genomics 14:225–239
Lammert F, Wang DQ-H, Wittenburg H et al (2002) Lith genes mucin accumulation, cholesterol crystallization and gallstone formation in A/J and AKR/J inbred mice. Hepatology 36:1145–1154
Miquel JF, Moreno M, Amigo L et al (2003) Expression and regulation of scavenger receptor class B type I (SR-BI) in gallbladder epithelium. Gut 52:1017–1024
Grünhage F, Acalovschi M, Tirziu S et al (2007) Increased gallstone risk in humans conferred by common variant of hepatic ATP-binding cassette transporter for cholesterol. Hepatology 46:793–801
Bouchard G, Nelson HM, Lammert F et al (1999) High-resolution maps of murine chromosome 2 region containing the cholesterol gallstone locus, Lith1. Mamm Genome 10:1070–1074
Kerjaschki D, Farquhar MG (1983) Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats. J Exp Med 157:667–686
Sahali D, Mulliez N, Chatelet F et al (1988) Characterization of a 280-kD protein restricted to the coated pits of the renal brush border and the epithelial cells of the yolk sac. Teratogenic effect of the specific monoclonal antibodies. J Exp Med 167:213–218
Yammani RR, Seetharam S, Seetharam B (2001) Cubilin and megalin expression and their interaction in the rat intestine: effect of thyroidectomy. Am J Physiol Endocrinol Metab 281:E900–E907
Van Praet O, Argraves WS, Morales CR (2003) Co-expression and interaction of cubilin and megalin in the adult male rat reproductive system. Mol Reprod Dev 64:129–135
Moestrup SK, Verroust PJ (2001) Megalin-and cubilin-mediated endocytosis of protein-bound vitamins, lipids and hormones in polarized epithelia. Annu Rev Nutr 21:407–428
Kozyraki R, Fyfe J, Verroust PJ et al (2001) Megalin-and cubilin-mediated endocytosis is a major pathway for the apical uptake of transferring in polarized epithelia. Proc Natl Acad Sci U S A 98:12491–12496
Kozyraki R (2001) Cubilin, a multifunctional epithelial receptor: an overview. J Mol Med 79:161–167
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25:402–408
Admirand WH, Small DM (1968) The physicochemical basis of cholesterol gallstone formation in man. J Clin Invest 47:1043–1052
Hofmann AF (2004) Milestones in liver disease. J Hepatol 41:195–200
Svenningsen AF, Gyllencreutz E, Aldskogius H (2006) Low-density lipoprotein receptor-related protein-2/megalin is expressed in oligodendrocytes in the mouse spinal cord white matter. J Comp Neurol 83:864–873
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Tsaroucha, A.K., Chatzaki, E., Lambropoulou, M. et al. Megalin and cubilin in the human gallbladder epithelium. Clin Exp Med 8, 165–170 (2008). https://doi.org/10.1007/s10238-008-0174-y
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DOI: https://doi.org/10.1007/s10238-008-0174-y