Skip Navigation



Human Molecular Genetics Advance Access published online on February 19, 2004
Human Molecular Genetics, doi:10.1093/hmg/ddh100
© 2004 by Oxford University Press
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
13/8/881    most recent
ddh100v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Pawlikowska, L.
Right arrow Articles by Freimer, N. B.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Pawlikowska, L.
Right arrow Articles by Freimer, N. B.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

©2004 Oxford University Press

Article

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

Ludmila Pawlikowska 1, Annemiek Groen 2, Elaine F. Eppens 2, Cindy Kunne 2, Roelof Ottenhoff 2, Norbert Looije 2, A. S. Knisely 3, Nigel P. Killeen 4, Laura N. Bull 5, Ronald P.J. Oude Elferink 2, and Nelson B. Freimer 6

1 UCSF Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, San Francisco, California, USA; Program in Biomedical Sciences, University of California - San Francisco, California, USA; AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
2 AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
3 Institute of Liver Studies, King's College Hospital, London, UK
4 Department of Microbiology and Immunology, University of California - San Francisco, California, USA
5 UCSF Liver Center Laboratory and Department of Medicine, San Francisco General Hospital, San Francisco, California, USA
6 UCLA Center for Neurobehavioral Genetics, Gonda Building, Room 3506, 695 Charles E. Young Drive South, Los Angeles, CA 90095-1761, USA


  Abstract

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 to 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 obscured by early onset of severe liver disease.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Proc. Natl. Acad. Sci. USAHome page
J. M. Stapelbroek, T. A. Peters, D. H. A. van Beurden, J. H. A. J. Curfs, A. Joosten, A. J. Beynon, B. M. van Leeuwen, L. M. van der Velden, L. Bull, R. P. Oude Elferink, et al.
ATP8B1 is essential for maintaining normal hearing
PNAS, June 16, 2009; 106(24): 9709 - 9714.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
C. C. Paulusma, D. R. de Waart, C. Kunne, K. S. Mok, and R. P. J. O. Elferink
Activity of the Bile Salt Export Pump (ABCB11) Is Critically Dependent on Canalicular Membrane Cholesterol Content
J. Biol. Chem., April 10, 2009; 284(15): 9947 - 9954.
[Abstract] [Full Text] [PDF]

Home page
 J. Lipid Res.Home page
M. T. Flowers, A. K. Groen, A. T. Oler, M. P. Keller, Y. Choi, K. L. Schueler, O. C. Richards, H. Lan, M. Miyazaki, F. Kuipers, et al.
Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet
J. Lipid Res., December 1, 2006; 47(12): 2668 - 2680.
[Abstract] [Full Text] [PDF]

Home page
 J. Med. Genet.Home page
S W C van Mil, R H J Houwen, and L W J Klomp
Genetics of familial intrahepatic cholestasis syndromes
J. Med. Genet., June 1, 2005; 42(6): 449 - 463.
[Abstract] [Full Text] [PDF]

Home page
 Hum Mol GenetHome page
L. Alvarez, P. Jara, E. Sanchez-Sabate, L. Hierro, J. Larrauri, M. C. Diaz, C. Camarena, A. De la Vega, E. Frauca, E. Lopez-Collazo, et al.
Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1
Hum. Mol. Genet., October 1, 2004; 13(20): 2451 - 2460.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.