Phenotypic characterization of Lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: soluble pronucleating proteins in gallbladder and hepatic biles

Background/Aims: Gallstone susceptibility is high in C57L inbred mice (males>females) and low in AKR mice, related to variant lithogenic (Lith) genes. We examined the relationship between biliary crystallization-promoting proteins and gallstone susceptibility. Methods: Biliary protein and lipid concentrations were determined at 0, 7, 14, 21, 28 and 56 days on a lithogenic diet. Results: Protein and soluble mucin concentrations in gallbladder biles increased markedly in males, but remained low in females of both strains and correlated with the cholesterol saturation index (CSI). In all groups, IgA and IgM concentrations decreased initially, but increased at later stages. There were no consistent changes in IgG concentrations, but aminopeptidase-N levels were higher in AKR than in C57L. During the lithogenic diet period, the CSI was ≥2 in C57L males, ≈1.5 in AKR males, and ≈1 in females of both strains. Taurodeoxycholate and taurochenodeoxycholate rose sharply in C57L, but remained low in AKR. Conclusions: Hydrophobic bile salts, cholesterol supersaturation, and possibly, high mucin concentrations are associated with gallstone formation. In vitro crystallization-promoting immunoglobulins and aminopeptidase-N do not appear to be major factors in murine gallstone pathogenesis, in line with the observation that genes encoding these proteins do not co-localize with any known Lith locus (Gastroenterology 2001;120:221).