Transgenic overexpression of Abcb11 enhances biliary bile salt outputs, but does not affect cholesterol cholelithogenesis in mice

Abstract

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.