Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump

Hepatology. 2009 Sep;50(3):948-56. doi: 10.1002/hep.23089.

Abstract

Bile salt export pump (BSEP; ATP-binding cassette, subfamily B, member 11) mutations in humans result in progressive familial intrahepatic cholestasis type 2, a fatal liver disease with greatly reduced bile flow. However in mice, Bsep knockout leads only to mild cholestasis with substantial bile flow and up-regulated P-glycoprotein genes (multidrug resistance protein 1a [Mdr1a] and Mdr1b). To determine whether P-glycoprotein is responsible for the relatively mild phenotype observed in Bsep knockout mice, we have crossed mouse strains knocked out for Bsep and the two P-glycoprotein genes and generated a triple knockout mouse. We found that a knockout of the three genes leads to a significantly more severe phenotype with impaired bile formation, jaundice, flaccid gallbladder, and increased mortality. The triple knockout mouse is the most severe genetic model of intrahepatic cholestasis yet developed.

Conclusion: P-glycoprotein functions as a critical compensatory mechanism, which reduces the severity of cholestasis in Bsep knockout mice.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency*
  • ATP Binding Cassette Transporter, Subfamily B / physiology
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters / genetics*
  • Animals
  • Bile / metabolism
  • Cholestasis, Intrahepatic / mortality
  • Cholestasis, Intrahepatic / pathology
  • Cholestasis, Intrahepatic / physiopathology*
  • Disease Models, Animal
  • Mice
  • Mice, Knockout

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 11
  • ATP-Binding Cassette Transporters
  • Abcb11 protein, mouse
  • P-glycoprotein 2
  • multidrug resistance protein 3