PHENOTYPIC CHARACTERIZATION OF LITH GENES THAT DETERMINE SUSCEPTIBILITY TO CHOLESTEROL CHOLELITHIASIS IN INBRED MICE - PHYSICAL-CHEMISTRY OF GALLBLADDER BILE

Lith genes control susceptibility to cholesterol gallstone formation i n inbred strains of mice on a lithogenic diet containing high fat, hig h cholesterol and 0.5% cholic acid. Our study defines the physical-che mical phenotypes of C57L, AKR, and (C57L x AKR) F-1 mouse gallbladder biles during 56 days on the lithogenic diet. We found enhanced cholest erol supersaturation, accumulation of mucin gel, and larger gallbladde rs in all C57L and F-1 mice, as well as more frequent gallstone format ion in male C57L and F-1 mice (80%) compared to females (40%) or AKR m ice (15%). In male C57L and F-1 mice, mucin gel accumulated at 3 days, followed by cholesterol supersaturation and phase separation of liqui d crystals, solid monohydrate crystals, and, in 43% of mice, anhydrous cholesterol crystals; whereas, in females, phase separations were del ayed 2 to 9 days, and anhydrous crystals did not form. In AKR mice, ch olesterol supersaturation and phase separations were infrequent and de layed, and gender did not influence the phenotype. Taurocholate invari ably replaced endogenous bile salts, especially tauro-beta-muricholate , with crystallization sequences matching taurocholate-containing mode l bile systems. We conclude: i) Lith genes determine biliary cholester ol supersaturation, mucin gel accumulation, gallbladder size, phase-se paration, and prevalence of cholesterol gallstones, ii) Identical phen otypes in C57L and F-1 mice indicate susceptibility to cholesterol gal lstones is genetically dominant, favoring males 2:1. iii) Mucin gel ac cumulation, crystallization, and stone formation are rare in AKR mice. This definition of the physical chemistry of lithogenesis should aid in further elucidation of the Lith genes and the proteins they encode.