Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice

Am J Physiol Gastrointest Liver Physiol. 2014 Apr 15;306(8):G670-6. doi: 10.1152/ajpgi.00334.2013. Epub 2014 Jan 30.

Abstract

Deficiency of ABCB4 is associated with several forms of cholestasis in humans. Abcb4(-/-) mice also develop cholestasis, but it remains uncertain what role other canalicular transporters play in the development of this disease. We examined the expression of these transporters in Abcb4(-/-) mice compared with their wild-type littermate controls at ages of 10 days and 3, 6, and 12 wk. Elevated plasma bile acid levels were already detected at 10 days and at all ages thereafter in Abcb4(-/-) mice. The expression of Bsep, Mrp2, Atp8b1, Abcg5, and Abcg8 liver proteins did not change at 10 days, but Bsep, Mrp2, and Atp8b1 were reduced, whereas Abcg5 and Abcg8 expression were increased in Abcb4(-/-) mice at all later ages. Lower bile acid concentrations were also detected in the bile of 6-wk-old Abcb4(-/-) mice. Immunofluorescence labeling revealed distorted canalicular architecture in the liver tissue by 12 wk in Abcb4(-/-) mice. Whereas Bsep and Mrp2 remained associated with the apical membrane, Atp8b1 was now localized in discrete punctuate structures adjacent to the canalicular membrane in these mice. Expression of Bsep mRNA was increased in the livers of 10-day-old Abcb4(-/-) mice, whereas Ost-α was decreased. By 12 wk, Bsep, Mrp2, and Abcg5 mRNA were all increased, whereas Ost-α and Ntcp were reduced. These findings indicate that canalicular transporters that determine the formation of bile are altered early in the development of cholestasis in Abcb4(-/-) mice and may contribute to the pathogenesis of cholestasis in this disorder.

Keywords: Abcb4; bile; canalicular transporter; cholestasis; phospholipid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B* / deficiency
  • ATP Binding Cassette Transporter, Subfamily B* / metabolism
  • ATP-Binding Cassette Sub-Family B Member 4
  • Animals
  • Bile Acids and Salts / biosynthesis*
  • Bile Acids and Salts / blood
  • Bile Canaliculi* / injuries
  • Bile Canaliculi* / metabolism
  • Bile Canaliculi* / pathology
  • Cholestasis, Intrahepatic / metabolism*
  • Membrane Transport Proteins* / analysis
  • Membrane Transport Proteins* / classification
  • Membrane Transport Proteins* / metabolism
  • Mice
  • Models, Animal

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • Bile Acids and Salts
  • Membrane Transport Proteins