LIPIDS AND LIPOPROTEINS
Regulation of ATP-binding Cassette Sterol Transporters ABCG5 and ABCG8 by the Liver X Receptors α and β*

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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) α and LXRβ. 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.

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Published, JBC Papers in Press, March 18, 2002, DOI 10.1074/jbc.M109927200

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This work was supported by grants from the Robert A. Welch Foundation (to D. J. M.), the Human Frontier Science Program (to D. J. M.), the Norwegian Research Council (to K. E. B.), Thoresen Foundation (to K. E. B.), and the D. W. Reynolds Foundation (to H. H. H.), by National Institutes of Health Grant HL20948 (to H. H. H.), and by the W. M. Keck Foundation (to H. H. H.). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

An associate of the Howard Hughes Medical Institute.