27-Hydroxycholesterol Is an Endogenous Ligand for Liver X Receptor in Cholesterol-loaded Cells

• Published in: The Journal of biological chemistry Vol. 276; no. 42; pp. 38378 - 38387
• Main Authors: Fu, Xuan, Menke, John G., Chen, Yuli, Zhou, Gaochao, MacNaul, Karen L., Wright, Samuel D., Sparrow, Carl P., Lund, Erik G.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.10.2001; American Society for Biochemistry and Molecular Biology
• Subjects: 27-hydroxycholesterol; ABCA1 gene; ABCG1 gene; ATP Binding Cassette Transporter 1; ATP Binding Cassette Transporter, Subfamily G, Member 1; ATP-Binding Cassette Transporters - metabolism; CCAAT-Enhancer-Binding Proteins - metabolism; Cells, Cultured; cholestenoic acid; Cholestenones - metabolism; Cholesterol - metabolism; Cholesterol, LDL - metabolism; CYP27 protein; DNA, Complementary - metabolism; DNA-Binding Proteins - metabolism; Dose-Response Relationship, Drug; Fibroblasts - metabolism; Gas Chromatography-Mass Spectrometry; Humans; Hydroxycholesterols - metabolism; Ligands; Liver X Receptors; Macrophages - metabolism; Orphan Nuclear Receptors; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Retinoic Acid - metabolism; Receptors, Thyroid Hormone - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Skin - metabolism; Sterol Regulatory Element Binding Protein 1; Time Factors; Transcription Factors; Transfection; Xanthomatosis, Cerebrotendinous - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M105805200

The nuclear receptors liver X receptor α (LXRα) (NR1H3) and LXRβ (NR1H2) are important regulators of genes involved in lipid metabolism, including ABCA1,ABCG1, and sterol regulatory element-binding protein-1c (SREBP-1c). Although it has been demonstrated that oxysterols are LXR ligands, little is known about the identity of the physiological activators of these receptors. Here we confirm earlier studies demonstrating a dose-dependent induction of ABCA1 and ABCG1 in human monocyte-derived macrophages by cholesterol loading. In addition, we show that formation of 27-hydroxycholesterol and cholestenoic acid, products of CYP27 action on cholesterol, is dependent on the dose of cholesterol used to load the cells. Other proposed LXR ligands, including 20(S)-hydroxycholesterol, 22(R)-hydroxycholesterol, and 24(S),25-epoxycholesterol, could not be detected under these conditions. A role for CYP27 in regulation of cholesterol-induced genes was demonstrated by the following findings. 1) Introduction of CYP27 into HEK-293 cells conferred an induction of ABCG1 and SREBP-1c; 2) upon cholesterol loading, CYP27-expressing cells induce these genes to a greater extent than in control cells; 3) in CYP27-deficient human skin fibroblasts, the induction of ABCA1 in response to cholesterol loading was ablated; and 4) in a coactivator association assay, 27-hydroxycholesterol functionally activated LXR. We conclude that 27-hydroxylation of cholesterol is an important pathway for LXR activation in response to cholesterol overload.