Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice.

Abstract

The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) cholesterol, and 0.5% (wt/wt) cholic acid. Strains C57L, SWR, and A were notable for a high prevalence of cholelithiasis; strains C57BL/6, C3H, and SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 exhibited no cholelithiasis after consuming the diet for 18 weeks. Genetic analysis of the difference in gallstone prevalence rates between strains AKR and C57L was carried out by using the AKXL recombinant inbred strain set and (AKR x C57L)F1 x AKR backcross mice. Susceptibility to gallstone formation was found to be a dominant trait determined by at least two genes. A major gene, named Lithl, mapped to mouse chromosome 2. When examined after 6 weeks on the lithogenic diet, the activity of hepatic 3-hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) was downregulated as expected in the gallstone-resistant strains, AKR and SJL, but this enzyme failed to downregulate in C57L and SWR, the gallstone-susceptible strains. This suggests that regulation of the rate-limiting enzyme in cholesterol biosynthesis may be pivotal in determining the occurrence and severity of cholesterol hypersecretion and hence lithogenicity of gallbladder bile. These studies indicate that genetic factors are critical in determining gallstone formation and that the genetic resources of the mouse model may permit these factors to be identified.Both atherosclerosis and cholelithiasis result from excess cholesterol; in the one case cholesterol is deposited in arterial walls, and in the other case cholesterol precipitates in the gallbladder. Both diseases are prevalent in cultures consuming a Western diet, and both can be induced in animal models by a diet high in cholesterol (1,2). In Western cultures, heart disease is the major cause of death, and gallstone disease is present in 10-40% of individuals over the age of 60 (3).Genetic factors apparently play an important role in the development of cholesterol gallstone disease. Among studies of gallstone formation in animals, Alexander and Portman (4) demonstrated that C57BL/6 mice are susceptible to cholelithiasis, but CBA mice are resistant. In both strains bile was supersaturated with cholesterol but not to the same degree (4). Fujihara et al. (5) reported that the prevalence of gallstones varied from 0% to 100% among six strains of laboratory mice.Evidence for the importance of genetic factors in human cholelithiasis is limited. Gallstone disease can be familial (6-11), and the bile from healthy sisters of female gallstone patients is more lithogenic than controls (11,12). In certain native populations of North and South America, a high percentage of adults develop cholesterol gallstones, suggesting common genetic factors (13,14).In previous studies, high fat plus high cholesterol diets produced atherosclerosis and gallstones in some strains of mice (15). In this report, we survey common inbred strains of mice for susceptibility to cholelith...

Gender-related differences in bile acid and sterol metabolism in outbred CD-1 mice fed low- and high-cholesterol diets

“…44 When lithogenic diets are fed to mice, they consume daily an amount of cholic acid that is equivalent to about three times what is normally present in their pool. 40,41 Although such diets have proved useful in identifying strains of mice with differing susceptibilities to cholesterol gallstone formation, it is likely that the gender differences in bile acid metabolism described here would no longer be manifest in mice fed a lithogenic diet.…”

“…34,[37][38][39] We also do not know how bile acid pool size and related parameters of bile acid metabolism change in cholesterol-fed mice, because most studies on this question have used cholesterol-rich diets containing added bile acid. 40,41 In the present studies we therefore used both outbred (CD-1) and inbred (C57BL/6 and 129Sv) strains of mice to obtain the first detailed characterization of the major parameters of bile acid metabolism in this species under conditions of a low and high dietary cholesterol intake.…”

Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy

“…For example, a genetic polymorphism that predisposes to gallstone formation has been identified in mice, 46 although a corresponding polymorphism has not been identified in humans to our knowledge. Genetic variations in other cholesterol transport proteins, cholesterol synthesis enzymes, and cholesterol nucleating and antinucleating proteins could account for some of the unexplained familial and ethnic clustering, 47 and deserve further study.…”

Spontaneous Gallstone Formation in Deer Mice: Interaction of Cholesterol, Bile Acids, and Dietary Fiber

“…It would also be interesting to subfractionate the serum cholesterol and examine the role of HDL versus VLDL in gallstone formation in deer mice, because low HDL cholesterol is positively correlated with gallstone prevalence in humans (Thijs et al, 1990), and is suggested in inbred mice (Khanuja et al, 1995). In addition, laboratory studies of biliary lipid secretion rates would help to further our understanding of the proposed supersaturation mechanism (Wang et al, 1999).…”

“…In addition, laboratory studies of biliary lipid secretion rates would help to further our understanding of the proposed supersaturation mechanism (Wang et al, 1999). Recent research into gallstone formation suggests a potential role for: 1) genetic inheritance of a predisposition to gallstones in laboratory mice (Alexander and Portman, 1987;Khanuja et al, 1995;Wang et al, 1997), 2) bacteria serving as a nidus for both cholesterol and pigment gallstone formation (Vitetta et al, 2000), and 3) melatonin as an inhibitor of cholelithiasis (Reiter et al, 2001). In the future, this animal model may contribute further insights towards the mechanisms underlying spontaneous gallstone formation and the development of dietary regimens for the prevention and treatment of human gallstones.…”