title: Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein.
abstract: Intrahepatic cholestasis is often associated with impairment of biliary bile acid secretion, a process mediated by the sister of P-glycoprotein (Spgp or Abcb11) also known as the bile salt export pump (Bsep). In humans, mutations in the Spgp gene are associated with a fatal childhood disease, type 2 progressive familial intrahepatic cholestasis (PFIC2). However in mice, the "knockout" of Spgp only results in mild cholestasis. In this study, we fed spgp(-/-) knockout mice with a cholic acid (CA)-supplemented diet to determine whether a more pronounced PFIC2-like phenotype could be induced. Such mice developed severe cholestasis characterized by jaundice, weight loss, elevated plasma bile acid, elevated transaminase, cholangiopathy (proliferation of bile ductules and cholangitis), liver necrosis, high mortality, and wide-ranging changes in the mRNA expression of major liver genes (16/36 examined). A surprising observation was that the bile acid output and bile flow in CA-fed mutant mice was significantly higher than anticipated. This suggests that the spgp(-/-) mice are able to utilize an alternative bile salt transport system. However, unlike Spgp, this system is insufficient to protect the knockout mice from cholestasis despite its high capacity. In conclusion, the spgp(-/-) mice provide a unique model to investigate molecular pathways associated with cholestasis and related diseases.
authors.affiliation: British Columbia Cancer Research Center, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
authors.forename: Renxue
authors.initials: R
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Lam
authors.forename: Lin
authors.initials: L
authors.lastname: Liu
authors.forename: Dana
authors.initials: D
authors.lastname: Forrest
authors.forename: Ibrahim M
authors.initials: IM
authors.lastname: Yousef
authors.forename: Diane
authors.initials: D
authors.lastname: Mignault
authors.forename: M James
authors.initials: MJ
authors.lastname: Phillips
authors.forename: Victor
authors.initials: V
authors.lastname: Ling
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002779:Cholestasis / Q000209:etiology*; D019826:Cholic Acid / Q000633:toxicity*; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006900:Hydroxylation; D008099:Liver / Q000473:pathology / Q000648:ultrastructure; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; D019826:Cholic Acid