Abstract
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 lithogenic diet containing 15% fat, 1% cholesterol, and 0.5% cholic acid, gallbladder bile displays rapid cholesterol supersaturation, mucin gel accumulation, 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. Lipid Res. 1997. 38: 1395;-1411). We have now determined the hepatic secretion rates of biliary lipids in fasting male and female C57L and AKR mice and the intercross (C57L x AKR)F(1) before and at frequent intervals during feeding the lithogenic diet for 56 days. Bile flow and biliary lipid secretion rates were measured in the first hour of an acute bile fistula and circulating bile salt pool sizes were determined by the "washout" technique after cholecystectomy. 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 increased biliary cholesterol and lecithin outputs, but bile salt outputs remained constant. Biliary coupling of cholesterol to lecithin increased approximately 30%, setting the biophysical conditions necessary for cholesterol phase separation in the gallbladder; and iii) no gender differences in lipid secretion rates were noted but male mice exhibited significantly more hydrophobic bile salt pools than females. We conclude that in gallstone-susceptible mice, Lith genes determine increased outputs of all biliary lipids but promote cholesterol hypersecretion disproportionately to lecithin and bile salt outputs thereby inducing lithogenic bile formation.
Highlights
The inbred C57L strain but not the AKR strain of mice carry Lith genes that determine cholesterol gallstone susceptibility
Because bile salts (BS) and Lec are necessary for Ch solubilization in bile [3, 4], lithogenic bile can be formed by relative excess Ch in relation to normal, high, or low amounts of these solubilizing agents
The most significant findings in the present study are three. i) Lithogenic hepatic biles precede the development of Ch gallstones in gallstone-susceptible mice, which supports the concept that changes in the hepatic secretion of biliary lipids are the primary precursors of Ch supersaturated bile in the gallbladder and Ch gallstone formation
Summary
The inbred C57L strain but not the AKR strain of mice carry Lith genes that determine cholesterol gallstone susceptibility. Susceptible mice display early Ch supersaturation, accumulation of mucin gel, and larger gallbladders as well as higher gallstone prevalence rates compared to resistant mice [19] In both male and female gallstone-susceptible mice, activity of hepatic HMG-CoA reductase controlling Ch biosynthesis failed to downregulate, and Ch 7␣-hydroxylase and sterol 27-hydroxylase, both regulatory enzymes in BS biosynthesis, became profoundly suppressed on the lithogenic diet (18, 20, accompanying paper). Because these different responses in mouse strains may be secondary to primary dysfunctions. These data provide important clues for exploring further the roles of Lith genes in pathogenesis of Ch cholelithiasis as well as for investigating the individual Lith gene phenotypes
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