Biochem. J. (2006) 398
(423–430) (Printed in Great Britain)
Targeted deletion of Gpbar1 protects mice from cholesterol gallstone formation
Galya VASSILEVA*1, 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, Jr†, Joseph HEDRICK* and Eric L. GUSTAFSON*
*Department of Discovery Technologies, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A., †Department of Cardiovascular/Metabolic Diseases, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A., and ‡Department of Drug Safety and Metabolism, Schering-Plough Research Institute, Kenilworth, NJ 07033, U.S.A.
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 7a-hydroxylase pathway.
Key words: bile acid, cholesterol, gall-bladder, gallstone, gene ablation, G-protein-coupled bile acid receptor 1 (Gpbar1).
Abbreviations used: BA, bile acid; CA, cholic acid; CBC, complete blood count; CDCA, chenodeoxycholic acid; CGD, cholesterol gallstone disease; CSI, cholesterol saturation index; Cyp27a1, sterol 27-hydroxylase; Cyp7a1, cholesterol 7a-hydroxylase; D2, type 2 iodothyroninedeiodinase; ES cell, embryonic stem cell; FAM, 6-carboxyfluorescein; FGF, fibroblast growth factor; FGFR4, FGF receptor 4; FTF, a-fetoprotein transcription factor; FXR, farnesoid X receptor; Gpbar1, G-protein-coupled BA receptor 1; GPCR, G-protein-coupled receptor; LXR, liver X receptor a; NSS, normal sheep serum; PXR, pregnane X receptor; SHP, small heterodimer partner; TEA, triethanolamine; TG, triacylglycerol.
1To whom correspondence should be addressed (email galya.vassileva@spcorp.com).
Received 10 April 2006/23 May 2006; accepted 26 May 2006
Published as BJ Immediate Publication 26 May 2006, doi:10.1042/BJ20060537
The Biochemical Society, London ©2006
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