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Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport
Author(s) -
Paulusma Coen C.,
Groen Annemiek,
Kunne Cindy,
HoMok Kam S.,
Spijkerboer Astrid L.,
Rudi de Waart D.,
Hoek Frans J.,
Vreeling Heleen,
Hoeben Kees A.,
van Marle Jan,
Pawlikowska Ludmila,
Bull Laura N.,
Hofmann Alan F.,
Knisely A. S.,
Oude Elferink Ronald P. J.
Publication year - 2006
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.21212
Subject(s) - progressive familial intrahepatic cholestasis , cholestasis , phospholipid , medicine , endocrinology , bile acid , chemistry , cholesterol , salt bridge , apical membrane , atpase , membrane , biochemistry , microbiology and biotechnology , biology , enzyme , mutant , transplantation , liver transplantation , gene
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. (H EPATOLOGY 2006;44:195–204.)