The Gpbar1 [G-protein-coupled BA (bile acid) receptor 1] is a recently identified cell-surface receptor that can bind and is activated by BAs, but its physiological role is unclear. Using targeted deletion of the Gpbar1 gene in mice, we show that the gene plays a critical role in the maintenance of bile lipid homoeostasis. Mice lacking Gpbar1 expression were viable, developed normally and did not show significant difference in the levels of cholesterol, BAs or any other bile constituents. However, they did not form cholesterol gallstones when fed a cholic acid-containing high-fat diet, and liver-specific gene expression indicated that Gpbar1-deficient mice have altered feedback regulation of BA synthesis. These results suggest that Gpbar1 plays a critical role in the formation of gallstones, possibly via a regulatory mechanism involving the cholesterol 7α-hydroxylase pathway.
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September 2006
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Research Article|
August 29 2006
Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation
Galya Vassileva;
Galya Vassileva
1
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
1To whom correspondence should be addressed (email [email protected]).
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Andrei Golovko;
Andrei Golovko
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Lisa Markowitz;
Lisa Markowitz
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Susan J. Abbondanzo;
Susan J. Abbondanzo
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Ming Zeng;
Ming Zeng
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Shijun Yang;
Shijun Yang
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Lizbeth Hoos;
Lizbeth Hoos
†Department of Cardiovascular/Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Glen Tetzloff;
Glen Tetzloff
†Department of Cardiovascular/Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Diane Levitan;
Diane Levitan
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Nicholas J. Murgolo;
Nicholas J. Murgolo
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Kevin Keane;
Kevin Keane
‡Department of Drug Safety and Metabolism, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Harry R. Davis, Jr;
Harry R. Davis, Jr
†Department of Cardiovascular/Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Joseph Hedrick;
Joseph Hedrick
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Eric L. Gustafson
Eric L. Gustafson
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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Publisher: Portland Press Ltd
Received:
April 10 2006
Revision Received:
May 23 2006
Accepted:
May 26 2006
Accepted Manuscript online:
May 26 2006
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2006
Biochem J (2006) 398 (3): 423–430.
Article history
Received:
April 10 2006
Revision Received:
May 23 2006
Accepted:
May 26 2006
Accepted Manuscript online:
May 26 2006
Citation
Galya Vassileva, Andrei Golovko, Lisa Markowitz, Susan J. Abbondanzo, Ming Zeng, Shijun Yang, Lizbeth Hoos, Glen Tetzloff, Diane Levitan, Nicholas J. Murgolo, Kevin Keane, Harry R. Davis, Joseph Hedrick, Eric L. Gustafson; Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation. Biochem J 15 September 2006; 398 (3): 423–430. doi: https://doi.org/10.1042/BJ20060537
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