Effects of bile salt flux variations on the expression of hepatic bile salt transporters in vivo in mice

J Hepatol. 2002 Nov;37(5):556-63. doi: 10.1016/s0168-8278(02)00247-7.

Abstract

Background/aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Animals
  • Bile Acids and Salts / metabolism*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cholestanetriol 26-Monooxygenase
  • Cholesterol 7-alpha-Hydroxylase / genetics*
  • DNA-Binding Proteins / genetics
  • Gene Expression / physiology
  • Liver / metabolism*
  • Male
  • Membrane Transport Proteins*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Organic Anion Transporters / genetics*
  • Organic Anion Transporters / metabolism
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Steroid Hydroxylases / genetics
  • Symporters
  • Transcription Factors / genetics

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, mouse
  • Bile Acids and Salts
  • Carrier Proteins
  • DNA-Binding Proteins
  • Membrane Transport Proteins
  • Organic Anion Transporters
  • Organic Anion Transporters, Sodium-Dependent
  • Receptors, Cytoplasmic and Nuclear
  • Symporters
  • Transcription Factors
  • nuclear receptor subfamily 0, group B, member 2
  • farnesoid X-activated receptor
  • sodium-bile acid cotransporter
  • Steroid Hydroxylases
  • Cholesterol 7-alpha-Hydroxylase
  • Cholestanetriol 26-Monooxygenase
  • Cyp27a1 protein, mouse