LITH1, A MAJOR GENE AFFECTING CHOLESTEROL GALLSTONE FORMATION AMONG INBRED STRAINS OF MICE

The prevalence of cholesterol gallstones differs among inbred strains of mice fed a diet containing 15% (wt/wt) dairy fat, 1% (wt/wt) choles terol, and 0.5% (wt/wt) cholic acid, Strains C57L, SWR, and A were not able for a high prevalence of cholelithiasis; strains C57BL/6, C3H, an d SJL had an intermediate prevalence; and strains SM, AKR, and DBA/2 e xhibited no cholelithiasis after consuming the diet for 18 weeks, Gene tic analysis of the difference in gallstone prevalence rates between s trains AKR and C57L was carried out by using the AKXL recombinant inbr ed strain set and (AKR x C57L)F-1 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 Lith1, mapped to mouse chromo some 2, When examined after 6 weeks on the lithogenic diet, the activi ty of hepatic 3 hydroxy-3-methylglutaryl-CoA reductase (EC 1.1.1.88) w as downregulated as expected in the gallstone-resistant strains, AKR a nd SJL, but this enzyme failed to downregulate in C57L and SWR, the ga llstone-susceptible strains. This suggests that regulation of the rate -limiting enzyme in cholesterol biosynthesis may be pivotal in determi ning the occurrence and severity of cholesterol hypersecretion and hen ce lithogenicity of gallbladder bile, These studies indicate that gene tic factors are critical in determining gallstone formation and that t he genetic resources of the mouse model may permit these factors to be identified.