Phenotypic characterization of Lith genes that determine susceptibility tocholesterol cholelithiasis in inbred mice: pathophysiology of biliary lipid secretion

The inbred C57L strain but not the AKR strain of mice carry Lith genes that determine cholesterol gallstone susceptibility, When C57L mice are fed a l ithogenic diet containing 15% fat, 1% cholesterol, and 0.5% cholic acid, ga llbladder bile displays rapid cholesterol supersaturation, mucin gel accumu lation, increases in hydrophobic bile salts, and rapid phase separation of solid and liquid crystals, all of which contribute to the high cholesterol gallstone prevalence rates (D. Q-H. Wang, B. Paigen, and M. C. Carey. J. Li pid Res. 1997, 38: 1395-111), We have now determined the hepatic secretion rates of biliary lipids in fasting male and female C57L and AKR mice and th e intercross (C57L x AKR)F-1 before and at frequent intervals during feedin g the lithogenic diet for 56 days, Bile flow and biliary lipid secretion ra tes were measured in the first hour of an acute bile fistula and circulatin g bile salt pool sizes were determined by the "washout" technique after cho lecystectomy, Compared with AKR mice, we found that i) C57L and F-1 mice on chow displayed significantly higher secretion rates of all biliary Lipids, and larger bile salt pool sizes, as well as higher bile salt-dependent and bile salt-independent flow rates; ii) the lithogenic diet further increase d biliary cholesterol and lecithin outputs, but bile salt outputs remained constant, Biliary coupling of cholesterol to lecithin increased approximate ly 30%, setting the biophysical conditions necessary for cholesterol phase separation in the gallbladder; and iii) no gender differences in lipid secr etion rates were noted but male mice exhibited significantly more hydrophob ic bile salt pools than females. We conclude that in gallstone-susceptible mice, Lith genes determine increased outputs of all biliary lipids but prom ote cholesterol hypersecretion disproportionately to lecithin and bile salt outputs thereby inducing lithogenic bile formation.