Stimulation of cholesterol excretion by the liver X receptor agonist requires ATP-binding cassette transporters G5 and G8.
Liver X receptor (LXR) is a nuclear receptor that plays a crucial role in orchestrating the trafficking of sterols between tissues. Treatment of mice with a potent and specific LXR agonist, T0901317, is associated with increased biliary cholesterol secretion, decreased fractional cholesterol absorption, and increased fecal neutral sterol excretion. Here we show that expression of two target genes of LXRalpha, the ATP-binding cassette (ABC) transporters Abcg5 and Abcg8, is required for both the increase in sterol excretion and the decrease in fractional cholesterol absorption associated with LXR agonist treatment. Mice expressing no ABCG5 and ABCG8 (G5G8(-/-) mice) and their littermate controls were treated for 7 days with T0901317. In wild type animals, treatment with the LXR agonist resulted in a 3-fold increase in biliary cholesterol concentrations, a 25% reduction in fractional cholesterol absorption, and a 4-fold elevation in fecal neutral sterol excretion. In contrast, the LXR agonist did not significantly affect biliary cholesterol levels, fractional cholesterol absorption, or neutral fecal sterol excretion in the G5G8(-/-) mice. Thus Abcg5 and Abcg8 are required for LXR agonist-associated changes in dietary and biliary sterol trafficking. These results establish a central role for ABCG5 and ABCG8 in promoting cholesterol excretion in vivo.
Yu
Liqing
L
McDermott Center for Human Growth and Development, Departments of Molecular Genetics and Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9046, USA.
York
Jennifer
J
von Bergmann
Klaus
K
Lutjohann
Dieter
D
Cohen
Jonathan C
JC
Hobbs
Helen H
HH
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000502:physiology*; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001646:Bile / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005243:Feces / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000032:analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000502:physiology*; D012855:Sitosterols / Q000378:metabolism; D013449:Sulfonamides; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D002784:Cholesterol; D004268:DNA-Binding Proteins; D006845:Hydrocarbons, Fluorinated; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012855:Sitosterols; D013449:Sulfonamides; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C025473:gamma-sitosterol