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Molecular and Cellular Biology, September 2004, p. 8154-8166, Vol. 24, No. 18
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.18.8154-8166.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Transcriptional Regulation of Human CYP27 Integrates Retinoid, Peroxisome Proliferator-Activated Receptor, and Liver X Receptor Signaling in Macrophages

Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine,¹ Department of Neurology, MedicalHealth Science Center, University of Debrecen, Debrecen, Hungary,³ Institute of Nutritional Sciences, University of Potsdam, Potsdam-Rehbrücke, Germany,² Department of Biomedical Science, University of Modena and Reggio Emilia, Modena, Italy,⁴ Department of Laboratory Medicine, Division of Clinical Chemistry, Huddinge University Hospital, Stockholm, Sweden⁵

Received 16 March 2004/ Returned for modification 5 April 2004/ Accepted 11 June 2004

Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPAR) and liver X receptor alpha (LXR) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPAR, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPAR-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPAR-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.

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