TY - JOUR
T1 - Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages
AU - Szanto, Attila
AU - Benko, Szilvia
AU - Szatmari, Istvan
AU - Balint, Balint L.
AU - Furtos, Ibolya
AU - Rühl, Ralph
AU - Molnar, Sandor
AU - Csiba, Laszlo
AU - Garuti, Rita
AU - Calandra, Sebastiano
AU - Larsson, Hanna
AU - Diczfalusy, Ulf
AU - Nagy, Laszlo
PY - 2004/9
Y1 - 2004/9
N2 - Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor alpha (LXRα) 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, PPARγ, 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-, PPARγ-, 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-PPARγ-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.
AB - Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor alpha (LXRα) 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, PPARγ, 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-, PPARγ-, 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-PPARγ-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.
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U2 - 10.1128/MCB.24.18.8154-8166.2004
DO - 10.1128/MCB.24.18.8154-8166.2004
M3 - Article
C2 - 15340076
AN - SCOPUS:4444337443
SN - 0270-7306
VL - 24
SP - 8154
EP - 8166
JO - Molecular and cellular biology
JF - Molecular and cellular biology
IS - 18
ER -