*Contributed equally to this work.
Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice
Article first published online: 20 MAY 2005
Volume 25, Issue 3, pages 604–612, June 2005
How to Cite
Hulzebos, C. V., Voshol, P. J., Wolters, H., Kruit, J. K., Ottenhof, R., Groen, A. K., Stellaard, F., Verkade, H. J. and Kuipers, F. (2005), Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice. Liver International, 25: 604–612. doi: 10.1111/j.1478-3231.2005.01036.x
- Issue published online: 20 MAY 2005
- Article first published online: 20 MAY 2005
- Received 15 January 2004, accepted 11 June 2004
- bile flow;
- bile formation;
- bile salt synthesis;
- cholate kinetics;
- cholehepatic shunt
Background/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 (Mdr2(−/−)) 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 2H4-cholate dilution. Results were related to expression of transport proteins in liver and intestine.
Results: During TUDC infusion, BSDF was increased by ∼50% and BSIF by ∼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.