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


CONCLUSIONS
P-glycoprotein functions as a critical compensatory mechanism, which reduces the severity of cholestasis in Bsep knockout mice.
Wang
Renxue
R
British Columbia Cancer Research Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
Chen
Huey-Ling
HL
Liu
Lin
L
Sheps
Jonathan A
JA
Phillips
M James
MJ
Ling
Victor
V
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency* / Q000502:physiology; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D001646:Bile / Q000378:metabolism; D002780:Cholestasis, Intrahepatic / Q000401:mortality / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D051379:Mice; D018345:Mice, Knockout; D000097202:ATP-Binding Cassette Sub-Family B Member 4
D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C490549:Abcb11 protein, mouse; C095122:multidrug resistance protein 3