In the search for an animal model of genetic determinants of cholesterol cholelithiasis, we found strain, gender and individual differences in mice. Male black (C57BL6J) mice had a 50% incidence of cholesterol gallstones after they consumed lithogenic food similar to that used by Tepperman et al. for 2 weeks, whereas similarly treated male agouti (CBA/J) mice and females of both strains were free of gallstones. The male and female mice of both strains were fertile at 8 weeks of age, and the male black mice were first susceptible to induction of gallstones at 24 weeks of age. Male agouti mice of the same age did not form gallstones until they had consumed the lithogenic food for 8 weeks. The gallbladder biles of both strains were supersaturated with cholesterol during the lithogenic regimen. The male agouti mice had much higher fractional turnover rates of [24-14C]cholic acid than did the male black mice. In spite of their small total cholate pools, the agouti mice had higher rates of new cholate synthesis than did the black mice. The rate of disappearance of [1,2-3H]cholesterol from the blood was higher in the male agouti than in the black mice. The gallbladders of the agouti mice contained less bile and weighed less empty than gallbladders of the black mice. They also did not increase in volume in response to the lithogenic diet as much as gallbladders of the black mice.
The difference in gallstone induction times between male and female black mice was as great as the difference between the two strains. In spite of their resistance to gallstone formation, the black females had gallbladder bile that was usually supersaturated with cholesterol; however, in one experiment their increase in biliary cholesterol concentration was delayed compared to that of males. The concentrations of esterified cholesterol in the liver were higher in the females than in the males, and the plasma cholesterol concentrations were lower. The pattern of metabolism of labeled cholate and cholesterol in the black females was intermediate between that of black male and agouti male mice. The empty gallbladders of the black females were heavier and increased more in volume during the lithogenic regimen than those of the black males.
The black males that formed gallstones had bile which was more supersaturated with cholesterol after 2 weeks on the lithogenic regimen than the black males which were free of stones. They also had lower rates of new cholate synthesis and lower concentrations of esterified cholesterol in the liver than the animals which were free of stones. After 4 and 8 weeks of the experiment, the concentrations of esterified cholesterol in the livers of agouti mice with gallstones were also less than in the livers of those without stones. Thus, resistance to cholesterol gallstone formation in mice may be related to increased activities of the liver in converting cholesterol to bile acids and to esterified cholesterol.