The mechanism of Abcg5/Abcg8 in biliary cholesterol secretion in mice

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

Department of Pediatrics Gastroenterology, Baylor College of Medicine, Houston, TX 77030

Corresponding Author: akosters{at}bcm.tmc.edu

The main player in biliary cholesterol secretion is the heterodimeric transporter complex, ABCG5/ABCG8, of which the function 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 lowering 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 to Abc8+/+ and Abcg8+/- mice, suggesting a reduced cholesterol content in the outer leaflet of the canalicular membrane. Isolation of canalicular membranes indeed 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.

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