Abstract
Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the autosomal recessive disorder sitosterolemia. Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxysterol receptors liver X receptor (LXR) alpha and LXRbeta. Diets containing high cholesterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine. This increase was also observed using synthetic ligands of LXR and its heterodimeric partner, the retinoid X receptor. In situ hybridization analyses of tissues from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation. In addition, expression of the LXR target gene ABCA1, previously implicated in the control of cholesterol absorption, was also dramatically up-regulated in jejunal enterocytes upon exposure to LXR agonists. These changes in ABC transporter gene expression were not observed in mice lacking LXRs. Furthermore, in the rat hepatoma cell line FTO2B, LXR-dependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by LXRs. The addition of ABCG5 and ABCG8 to the growing list of LXR target genes further supports the notion that LXRs serve as sterol sensors to coordinately regulate sterol catabolism, storage, efflux, and elimination.
Highlights
Cholesterol homeostasis is maintained by a series of regulatory pathways to control the synthesis of endogenous cholesterol, the absorption of dietary sterol, and the elimination of cholesterol and its catabolic end products, bile acids
1 The abbreviations used are: sterolregulatory element-binding proteins (SREBPs), sterol-regulatory elementbinding protein; ABC, ATP-binding cassette; LXR, liver X receptor; SREBP-2, which control the production of key enzymes in cholesterol biosynthesis, and the liver X receptors LXR␣ and LXR, which regulate the expression of genes involved in cholesterol efflux, storage, catabolism, and elimination
Increasing evidence suggests that the retinoid X receptors (RXRs)/LXR heterodimer serves as a sensor that responds to high intracellular sterol concentrations by increasing the expression of genes that reduce the cellular sterol load
Summary
Nuclear receptor agonists were obtained from the following sources. Fenofibrate, pregnenolone ␣-carbonitrile, and chenodeoxycholic acid were purchased from Sigma; troglitazone was a generous gift from Roger Unger (University of Texas Southwestern Medical Center at Dallas); LG268 and GW4064 were provided by Richard Heyman and Raju Mohan (X-Ceptor Therapeutics, Inc., San Diego, CA); and T0901317 was supplied by Bei Shan (Tularik, South San Francisco, CA). Sodium compactin, and delipidated fetal calf serum were prepared as described previously [24, 25]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
