REGULATION OF BILIARY LIPID SECRETION BY MDR2 P-GLYCOPROTEIN IN THE MOUSE

Disruption of the mdr2 gene in mice leads to a complete absence of pho spholipid from bile (Smit, J. J. M., et al. 1993. Cell. 75:451-462). W e have investigated the control of both mdr2 P-glycoprotein (Pgp) expr ession and bile salt secretion on biliary lipid secretion in the mouse . Lipid secretion was monitored at various bile salt output rates in w ild-type mice (+/+), heterozygotes (+/-), and homozygotes (-/-) for md r2 gene disruption. In (-/-) mice, phospholipid secretion was negligib le at all bile salt output rates. In (+/-) mice, a curvilinear relatio n between bile salt and phospholipid secretion was observed similar to that in (+/ +) mice; however, at all bile salt secretion rates phosph olipid secretion was reduced compared to (+/+)mice, indicating that md r2 Pgp exerts a strong control over secretion. Infusion of increasing amounts of taurocholate up to maximal secretory rate led to a decline in the phospholipid and cholesterol secretion in both (+/+) and (+/-) mice in accordance to what has been observed in other species. In cont rast, in (-/-) mice cholesterol secretion increased under these condit ions while phospholipid output remained extremely low. The increased c holesterol secretion may represent extraction of cholesterol from the canalicular plasma membrane by taurocholate micelles as opposed to the concomitant secretion of both phospholipid and cholesterol in the pre sence of a functional mdr2 Pgp. Increased bile flow in (-/-) mice coul d be attributed completely-to an increase in the bile salt-independent fraction and may therefore be caused by the bile duct proliferation i n these mice.