Bile duct proliferation associated with bile salt-induced hypercholeresis in Mdr2 P-glycoprotein-deficient mice.
OBJECTIVE
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 approximately 50% and BSIF by approximately 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.
Hulzebos
Christian V
CV
Center for Liver, Digestive and Metabolic Diseases, Department of Pediatrics, University Hospital Groningen, Groningen, The Netherlands.
Voshol
Peter J
PJ
Wolters
Henk
H
Kruit
Janine K
JK
Ottenhof
Roelof
R
Groen
Albert K
AK
Stellaard
Frans
F
Verkade
Henkjan J
HJ
Kuipers
Folkert
F
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001649:Bile Duct Diseases / Q000378:metabolism* / Q000473:pathology*; D001652:Bile Ducts / Q000473:pathology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D020355:Cholates / Q000493:pharmacokinetics; D003903:Deuterium; D005704:Gallbladder / Q000378:metabolism; D007422:Intestines / Q000502:physiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D020355:Cholates; D003903:Deuterium; D008562:Membrane Glycoproteins; D029363:Organic Anion Transporters, Sodium-Dependent; D010743:Phospholipids; D012333:RNA, Messenger; D027981:Symporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter