Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice

Baekground/Aims: Bile flow consists of bile salt-dependent bile flow (BSDF), generated by canalicular secretion of bile salts, and bile salt-independent flow (BSIF), probably of combined canalicular and ductular origin. Bile salt transport proteins have been identified in cholangiocytes suggesting a role in control of BSDF and/or in control of bile salt synthesis, through cholehepatic shunting. Methods: We studied effects of bile duct proliferation under non-cholestatic conditions in multidrug resistance-2 P-glycoprotein (Abcb4)-deficient multidrug resistance gene-2 (Mdl-2((-/-))) mice. BSDF and BSIF were determined in wild-type and Mdr2((-/-)) mice during infusion of step-wise increasing dosages of tauroursodeoxycholate (TUDC). Cholate synthesis rate was determined by H-2(4)-cholate dilution. Results were related to expression of transport proteins in liver and intestine. Results: During TUDC infusion, BSDF was increased by similar to 50% and BSIF by similar to 100% in Mdr2((-/-)) mice compared with controls. Cholate synthesis rate was unaffected in Mdr2((-/-)) mice. Hepatic expression of the apical sodium-dependent bile salt transporter (Asbt), its truncated form (tAsbt) and the multidrug resistance-related protein 3 were upregulated in Mdr2((-/-)) mice. Conclusions: Bile duct proliferation in Mdr2((-/-)) mice enhances cholehepatic shunting of bile salts, which is associated with a disproportionally high bile flow but does not affect bile salt synthesis.