Khanuja B, Cheah Y C, Hunt M, Nishina P M, Wang D Q, Chen H W, Billheimer J T, Carey M C, Paigen B
Jackson Laboratory, Bar Harbor, ME 04609, USA.
Proc Natl Acad Sci U S A. 1995 Aug 15;92(17):7729-33. doi: 10.1073/pnas.92.17.7729.
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 Lith1, 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.
在喂食含15%（重量/重量）乳脂肪、1%（重量/重量）胆固醇和0.5%（重量/重量）胆酸饮食的近交系小鼠中，胆固醇胆结石的患病率有所不同。C57L、SWR和A品系的胆结石患病率较高；C57BL/6、C3H和SJL品系的患病率处于中等水平；而SM、AKR和DBA/2品系在食用该饮食18周后未出现胆结石。利用AKXL重组近交系小鼠和（AKR×C57L）F1×AKR回交小鼠，对AKR和C57L品系之间胆结石患病率差异进行了遗传分析。发现胆结石形成易感性是一种由至少两个基因决定的显性性状。一个名为Lith1的主要基因定位于小鼠2号染色体。在致石饮食喂养6周后进行检查时，抗胆结石品系AKR和SJL中，肝脏3-羟基-3-甲基戊二酰辅酶A还原酶（EC 1.1.1.88）的活性如预期那样下调，但在胆结石易感品系C57L和SWR中，该酶未能下调。这表明胆固醇生物合成限速酶的调节可能在决定胆固醇过度分泌的发生和严重程度以及胆囊胆汁的致石性方面起关键作用。这些研究表明，遗传因素在决定胆结石形成中至关重要,并且小鼠模型的遗传资源可能有助于识别这些因素。
