Stimulation of Cholesterol Excretion by the Liver X Receptor Agonist Requires ATP-binding Cassette Transporters G5 and G8

• Published in: The Journal of biological chemistry 2003-05, Vol.278 (18), p.15565-15570
• Main Authors: Yu, Liqing, York, Jennifer, von Bergmann, Klaus, Lutjohann, Dieter, Cohen, Jonathan C., Hobbs, Helen H.
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - pharmacology; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters - physiology; Bile - metabolism; Cholesterol - metabolism; DNA-Binding Proteins; Feces - chemistry; Hydrocarbons, Fluorinated; Lipoproteins - physiology; Liver - metabolism; Liver X Receptors; Mice; Mice, Inbred C57BL; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear - agonists; Receptors, Cytoplasmic and Nuclear - physiology; RNA, Messenger - analysis; Sitosterols - metabolism; Sulfonamides
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M301311200

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 LXRα, the ATP-binding cassette (ABC) transportersAbcg5 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.