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Journal of Lipid Research, Vol. 47, 1959-1966, September 2006
Copyright © 2006 by American Society for Biochemistry and Molecular Biology

The mechanism of ABCG5/ABCG8 in biliary cholesterol secretion in mice¹

Astrid Kosters^2,*, Cindy Kunne^*, Norbert Looije^*, Shailendra B. Patel, Ronald P. J. Oude Elferink^* and Albert K. Groen^*

^* AMC Liver Center, Academic Medical Center, Amsterdam, The Netherlands
Division of Endocrinology, Metabolism, and Clinical Nutrition, Medical College of Wisconsin, Milwaukee, WI

¹ Part of this study was presented at the American Association for the Study of Liver Diseases Annual Meeting, Boston, Massachusetts, October 24–28, 2003 and was published as an abstract in Hepatology 2003.(38 Suppl. 1): 387A.

Published, JLR Papers in Press, June 1, 2006.

² To whom correspondence should be addressed. e-mail: akosters{at}bcm.tmc.edu

The main player in biliary cholesterol secretion is the heterodimeric transporter complex, ABCG5/ABCG8, the function of which is necessary for the majority of sterols secreted into bile. It is not clear whether the primary step in this process is flopping of cholesterol from the inner to the outer leaflet of the canalicular membrane, with desorption by mixed micelles, or decreasing of the activation energy required for cholesterol desorption from the outer membrane leaflet. In this study, we investigated these mechanisms by infusing Abcg8^+/+, Abcg8^+/–, and Abcg8^–/– mice with hydrophilic and hydrophobic bile salts. In Abcg8^–/– mice, this failed to substantially stimulate biliary cholesterol secretion. Infusion of the hydrophobic bile salt taurodeoxycholate also resulted in cholestasis, which was induced in Abcg8^–/– mice at a much lower infusion rate compared with Abc8^–/– and Abcg8^+/– mice, suggesting a reduced cholesterol content in the outer leaflet of the canalicular membrane. Indeed, isolation of canalicular membranes revealed a reduction of 45% in cholesterol content under these conditions in Abcg8^–/– mice. Our data support the model that ABCG5/ABCG8 primarily play a role in flopping cholesterol (and sterols) from the inner leaflet to the outer leaflet of the canalicular membrane.

Supplementary key words liver • canalicular membrane • bile salt infusion • diosgenin

Abbreviations: PC, phosphatidylcholine; TC, taurocholic acid; TDC, taurodeoxycholic acid; TUDC, tauroursodeoxycholic acid

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