Compensatory role of P-glycoproteins in knockout mice lacking the bile salt export pump
Journal
Hepatology
Journal Volume
50
Journal Issue
3
Pages
948-956
Date Issued
2009
Author(s)
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. Copyright ? 2009 by the American Association for the Study of Liver Diseases.
SDGs
Other Subjects
ABC transporter; ABC transporter subfamily B member 11; glycoprotein P; multidrug resistance protein 1; multidrug resistance protein 1a; multidrug resistance protein 1b; protein bcl 2; unclassified drug; ABC transporter; Abcb11 protein, mouse; glycoprotein P; multidrug resistance protein 3; P glycoprotein 2; P-glycoprotein 2; animal experiment; animal tissue; article; bile flow; controlled study; disease severity; female; gallbladder disease; growth retardation; hepatomegaly; intrahepatic cholestasis; jaundice; knockout mouse; lymphocytic infiltration; mortality; mouse; mouse strain; nonhuman; null allele; phenotype; polymerase chain reaction; priority journal; protein function; upregulation; Western blotting; animal; bile; disease model; genetics; intrahepatic cholestasis; metabolism; mouse mutant; pathology; pathophysiology; physiology; Animals; ATP-Binding Cassette Transporters; Bile; Cholestasis, Intrahepatic; Disease Models, Animal; Mice; Mice, Knockout; P-Glycoproteins
Type
journal article