Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice.
OBJECTIVE
Expression of hepatic bile salt transporters is partly regulated by bile salts via activation of nuclear farnesoid X-activated receptor (Fxr). We investigated the physiological relevance of this regulation by evaluating transporter expression in mice experiencing different transhepatic bile salt fluxes.


METHODS
Bile salt flux was manipulated by dietary supplementation with taurocholate (0.5% w/w) or cholestyramine (2% w/w) or by disruption of the cholesterol 7alpha-hydroxylase-gene (Cyp7A(-/-) mice) leading to reduced bile salt pool size. Expression of hepatic transporters was assessed (polymerase chain reaction (PCR), immunoblotting, and immunohistochemistry).


RESULTS
Biliary bile salt secretion was increased (+350%) or decreased (-50%) after taurocholate or cholestyramine feeding, respectively, but plasma bile salt concentrations and hepatic Fxr expression were not affected. The bile salt uptake system Na(+)-taurocholate co-transporting polypeptide (Ntcp) and organic anion transporting polypeptide-1 (Oatp1) were down-regulated by taurocholate and not affected by cholestyramine feeding. Cyp7A(-/-) mice did not show altered Ntcp or Oatp1 expression. Canalicular bile salt export pump (Bsep) was up-regulated by 65% in taurocholate-fed mice, and slightly down-regulated in Cyp7A(-/-) mice.


CONCLUSIONS
Large variations in hepatic bile salt flux have minor effects on expression of murine Ntcp and Bsep in vivo, suggesting that these transporters are abundantly expressed and able to accommodate a wide range of 'physiological' bile salt fluxes.
Wolters
Henk
H
Center for Liver, Digestive and Metabolic Diseases, Groningen University Institute for Drug Exploration, Groningen, The Netherlands. h.wolters@med.rug.nl
Elzinga
Baukje M
BM
Baller
Julius F W
JF
Boverhof
Renze
R
Schwarz
Margrit
M
Stieger
Bruno
B
Verkade
Henkjan J
HJ
Kuipers
Folkert
F
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000502:physiology; D008099:Liver / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D027981:Symporters; D014157:Transcription Factors / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D053493:Cholestanetriol 26-Monooxygenase; D002790:Cholesterol 7-alpha-Hydroxylase; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D027361:Organic Anion Transporters; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C490549:Abcb11 protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C071908:sodium-bile acid cotransporter; C506832:Cyp27a1 protein, mouse