Roles of ATP-binding cassette tranporters G5 and G8 in liver X receptor-mediated sterol trafficking

by York, Jennifer L.

THE ROLES OF ATP-BINDING CASSETTE TRANSPORTERS G5 AND G8 IN LIVER X RECEPTOR-MEDIATED STEROL TRAFFICKING Publication No. ___________ Jennifer Lynn York The University of Texas Southwestern Medical Center at Dallas, 2004 Supervising Professor: Helen H. Hobbs, M. D. The liver X receptor (LXR) is a nuclear receptor that plays a critical role in orchestrating the trafficking of sterols between tissues. Treatment of wild type mice with a potent and specific nonsteroidal LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. The following studies show that expression of two target genes of LXR?, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for the increase in sterol excretion, the decrease in fractional cholesterol absorption, and the increase in fecal neutral sterol excretion associated with LXR agonist treatment. Mice lacking ABCG5 and ABCG8 (G5G8-/mice) and wild type littermate controls were treated for 7 days with T0901317. In control animals, the LXR agonist produced a 3-fold increase in biliary cholesterol concentration, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, treatment of G5G8-/mice with the LXR agonist did not significantly affect any of these parameters. These results demonstrate that ABCG5 and ABCG8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking and that increased expression of these proteins promotes cholesterol excretion in vivo. 4