TY  - JOUR
A1  - Szanto, Attila
A1  - Benko, Szilvia
A1  - Szatmari, István
A1  - Balint, Balint L.
A1  - Furtos, Ibolya
A1  - Ruehl, Ralph
A1  - Molnar, Sandor
A1  - Csiba, Laszlo
A1  - Garuti, Rita
A1  - Calandra, Sebastiano
A1  - Larsson, Hanna
A1  - Diczfalusy, Ulf
A1  - Nagy, Laszlo
T1  - Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages
N2  - Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) 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, PPARgamma, 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-, PPARgamma-, 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-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages
Y1  - 2004
SN  - 0270-7306
ER  -