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Human Molecular Genetics Advance Access originally published online on February 19, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 8 881-892
DOI: 10.1093/hmg/ddh100
Human Molecular Genetics, Vol. 13, No. 8 © Oxford University Press 2004; all rights reserved

A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion

Ludmila Pawlikowska1,2,4, Annemiek Groen4, Elaine F. Eppens4, Cindy Kunne4, Roelof Ottenhoff4, Norbert Looije4, A.S. Knisely5, Nigel P. Killeen3, Laura N. Bull1, Ronald P.J. Oude Elferink4 and Nelson B. Freimer6,*

1UCSF Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, San Francisco, California, USA, 2Program in Biomedical Sciences and 3Department of Microbiology and Immunology, University of California, San Francisco, California, USA, 4AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands, 5Institute of Liver Studies, King's College Hospital, London, UK and 6Center for Neurobehavioral Genetics, University of California, Los Angeles, California, USA

Received January 22, 2004; Accepted February 10, 2004

Mutations in ATP8B1, a broadly expressed P-type ATPase, result, through unknown mechanisms, in disorders of bile secretion. These disorders vary in severity from mild and episodic to progressive with liver failure. We generated Atp8b1G308V/G308V mutant mice, which carry a mutation orthologous to that present in homozygous form in patients from the Amish index kindred for severe ATP8B1 disease. In contrast to human patients, Atp8b1G308V/G308V mice had unimpaired bile secretion and no liver damage, but showed mild abnormalities including depressed weight at weaning and elevated serum bile salt levels. We challenged the hepatobiliary metabolism of Atp8b1G308V/G308V mice by administering exogenous bile salts. Upon bile salt feeding, Atp8b1G308V/G308V mice, but not wild-types, demonstrated serum bile salt accumulation, hepatic injury and expansion of the systemic bile salt pool. Unexpectedly, this failure of bile salt homeostasis occurred in the absence of any defect in hepatic bile secretion. Upon infusion of a hydrophobic bile salt, wild-type mice developed cholestasis while Atp8b1G308V/G308V mice maintained high biliary output and more extensively rehydroxylated the infused bile salt. Increased bile salt hydroxylation, which reduces bile salt toxicity, may explain the milder phenotype in Atp8b1G308V/G308V mice compared with humans with the equivalent mutation. These results demonstrate the key role of Atp8b1 in bile salt homeostasis and highlight the importance of bile salt hydroxylation in the prevention of cholestasis. The mouse phenotype reveals that loss of Atp8b1 disrupts bile salt homeostasis without impairment of canalicular bile secretion; in humans this process is likely to be obscured by early onset of severe liver disease.

* To whom correspondence should be addressed at: UCLA Center for Neurobehavioral Genetics, Gonda Building, Room 3506, 695 Charles E. Young Drive South, Los Angeles, CA 90095-1761, USA. Tel: +1 3107949571; Fax: +1 3107949613; Email: nfreimer{at}mednet.ucla.edu


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