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

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Author: Hulzebos, C.V. · Voshol, P.J. · Wolters, H. · Kruit, J.K. · Ottenhof, R. · Groen, A.K. · Stellaard, F. · Verkade, H.J. · Kuipers, F.
Type:article
Date:2005
Institution: TNO Preventie en Gezondheid
Source:Liver International, 3, 25, 604-612
Identifier: 238519
doi: doi:10.1111/j.1478-3231.2005.01036.x
Keywords: Bile flow · Bile formation · Bile salt synthesis · Cholangiocyte · Cholate kinetics · Cholehepatic shunt · beta actin · bile salt · binding protein · carrier protein · chenodeoxycholic acid · cholic acid · deoxycholic acid · glycoprotein P · ileal bile salt binding protein · lithocholic acid · messenger RNA · multidrug resistance protein 2 · multidrug resistance protein 3 · muricholic acid · tauroursodeoxycholic acid · unclassified drug · animal experiment · animal model · animal tissue · bile acid synthesis · cell proliferation · controlled study · dilution · immunohistochemistry · in vivo study · intestine mucosa · intrahepatic bile duct · kinetics · liver parenchyma · male · mouse · nonhuman · nucleotide sequence · protein analysis · protein deficiency · protein expression · upregulation · Western blotting · wild type · Animals · Bile Acids and Salts · Bile Duct Diseases · Bile Ducts · Carrier Proteins · Cell Division · Cholates · Deuterium · Gallbladder · Intestines · Membrane Glycoproteins · Mice · Mice, Mutant Strains · Organic Anion Transporters, Sodium-Dependent · P-Glycoproteins · Phospholipids · RNA, Messenger · Symporters

Abstract

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. © Blackwell Munksgaard 2005. Chemicals / CAS: carrier protein, 80700-39-6; chenodeoxycholic acid, 474-25-9; cholic acid, 32500-01-9, 361-09-1, 81-25-4; deoxycholic acid, 83-44-3; lithocholic acid, 434-13-9; multidrug resistance protein 2, 256503-65-8; multidrug resistance protein 3, 231947-64-1; muricholic acid, 39016-49-4; tauroursodeoxycholic acid, 14605-22-2; bile acid binding proteins; Bile Acids and Salts; Carrier Proteins; Cholates; Deuterium, 7782-39-0; Membrane Glycoproteins; Organic Anion Transporters, Sodium-Dependent; P-glycoprotein 2; P-Glycoproteins; Phospholipids; RNA, Messenger; sodium-bile acid cotransporter, 145420-23-1; Symporters