title: Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.
abstract: Progressive familial intrahepatic cholestasis type 1 (PFIC1, Byler disease, OMIM 211600) is a severe inherited liver disease caused by mutations in ATP8B1. ATP8B1 is a member of the type 4 subfamily of P-type ATPases, which are phospholipid flippases. PFIC1 patients generally develop end-stage liver disease before the second decade of life. The disease is characterized by impaired biliary bile salt excretion, but the mechanism whereby impaired ATP8B1 function results in cholestasis is unclear. In a mouse model for PFIC1, we observed decreased resistance of the hepatocanalicular membrane to hydrophobic bile salts as evidenced by enhanced biliary recovery of phosphatidylserine, cholesterol, and ectoenzymes. In liver specimens from PFIC1 patients, but not in those from control subjects, ectoenzyme expression at the canalicular membrane was markedly deficient. In isolated mouse livers Atp8b1 deficiency impaired the transport of hydrophobic bile salts into bile. In conclusion, our study shows that Atp8b1 deficiency causes loss of canalicular phospholipid membrane asymmetry that in turn renders the canalicular membrane less resistant toward hydrophobic bile salts. The loss of phospholipid asymmetry may subsequently impair bile salt transport and cause cholestasis.
authors.affiliation: Amsterdam Liver Center, Department of Experimental Hepatology, Academic Medical Center, Amsterdam, the Netherlands. c.c.paulusma@amc.uva.nl
authors.forename: Coen C
authors.initials: CC
authors.lastname: Paulusma
authors.forename: Annemiek
authors.initials: A
authors.lastname: Groen
authors.forename: Cindy
authors.initials: C
authors.lastname: Kunne
authors.forename: Kam S
authors.initials: KS
authors.lastname: Ho-Mok
authors.forename: Astrid L
authors.initials: AL
authors.lastname: Spijkerboer
authors.forename: D
authors.initials: D
authors.lastname: Rudi de Waart
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Hoek
authors.forename: Heleen
authors.initials: H
authors.lastname: Vreeling
authors.forename: Kees A
authors.initials: KA
authors.lastname: Hoeben
authors.forename: Jan
authors.initials: J
authors.lastname: van Marle
authors.forename: Ludmila
authors.initials: L
authors.lastname: Pawlikowska
authors.forename: Laura N
authors.initials: LN
authors.lastname: Bull
authors.forename: Alan F
authors.initials: AF
authors.lastname: Hofmann
authors.forename: A S
authors.initials: AS
authors.lastname: Knisely
authors.forename: Ronald P J
authors.initials: RP
authors.lastname: Oude Elferink
mesh_terms: D000251:Adenosine Triphosphatases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001648:Bile Canaliculi / Q000378:metabolism* / Q000648:ultrastructure; D001692:Biological Transport; D015153:Blotting, Western; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002780:Cholestasis, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D002855:Chromatography, Thin Layer; D004195:Disease Models, Animal; D057927:Hydrophobic and Hydrophilic Interactions; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008854:Microscopy, Electron; D049294:Phospholipid Transfer Proteins
chemical_list: D001647:Bile Acids and Salts; D049294:Phospholipid Transfer Proteins; D000251:Adenosine Triphosphatases; C491742:Atp8b1 protein, mouse