Beth Israel Deaconess Medical Center, Harvard Medical School and Harvard Digestive Diseases Center, Boston, MA 02215, USA.
Eur J Clin Invest. 2010 Jun;40(6):541-51. doi: 10.1111/j.1365-2362.2010.02300.x. Epub 2010 Apr 28.
Cholesterol gallstone disease is a complex genetic trait and induced by multiple but as yet unknown genes. A major Lith gene, Lith1 was first identified on chromosome 2 in gallstone-susceptible C57L mice compared with resistant AKR mice. Abcb11, encoding the canalicular bile salt export pump in the hepatocyte, co-localizes with the Lith1 QTL region and its hepatic expression is significantly higher in C57L mice than in AKR mice.
To investigate whether Abcb11 influences cholesterol gallstone formation, we created an Abcb11 transgenic strain on the AKR genetic background and fed these mice with a lithogenic diet for 56 days.
We excluded functionally relevant polymorphisms of the Abcb11 gene and its promoter region between C57L and AKR mice. Overexpression of Abcb11 significantly promoted biliary bile salt secretion and increased circulating bile salt pool size and bile salt-dependent bile flow rate. However, biliary cholesterol and phospholipid secretion, as well as gallbladder size and contractility were comparable in transgenic and wild-type mice. At 56 days on the lithogenic diet, cholesterol saturation indexes of gallbladder biles and gallstone prevalence rates were essentially similar in these two groups of mice.
Overexpression of Abcb11 augments biliary bile salt secretion, but does not affect cholelithogenesis in mice.
胆固醇胆石病是一种复杂的遗传特征，由多个但尚未明确的基因引起。Lith1 是首个在易患胆结石的 C57L 小鼠而非耐药 AKR 小鼠的 2 号染色体上被鉴定出的主要 Lith 基因。编码肝细胞管腔胆汁盐输出泵的 Abcb11 与 Lith1 QTL 区域共定位，其在 C57L 小鼠中的肝表达明显高于 AKR 小鼠。
为了研究 Abcb11 是否影响胆固醇胆石形成，我们在 AKR 遗传背景下创建了 Abcb11 转基因品系，并在该品系上用致石饮食喂养 56 天。
我们排除了 C57L 和 AKR 小鼠之间 Abcb11 基因及其启动子区域的功能相关多态性。Abcb11 的过表达显著促进了胆汁中胆汁盐的分泌，增加了循环胆汁盐池的大小和胆汁盐依赖性胆汁流量。然而，转基因和野生型小鼠的胆汁胆固醇和磷脂分泌、胆囊大小和收缩性相似。在致石饮食 56 天时，两组小鼠的胆囊胆汁胆固醇饱和度指数和胆结石患病率基本相似。
Abcb11 的过表达增强了胆汁中胆汁盐的分泌，但不影响小鼠的胆石形成。
